JPS6144872A - Pyrimidine derivative and drug composition containing it - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I {R<1> is H, (substituted) aryl, or N-containing heterocyclic group; R<2> is =N-R<2>, NRa<2>Rb<2>, (substituted) N-containing heterocyclic group, or O-R<2>[Ra<2> is (substituted)aryl; Rb<2> is H, or alkyl]; R<3> is H, alkyl or does not exist; R<4> is (substituted)imino, alkyl, H, halogen, etc.; R<5> is H, alkyl, or does not exist; R<6> is H, alkyl, (substituted)aryl, etc.}, and its salt. EXAMPLE:3,4-Dihydro-6-( 3,4-dimethoxyphenyl )3-methyl-4-( 2,4,6-trimethylphenylimino)pyrimidine. USE:An antihypertensive, cerebrovascular vasodilator, inhibitor of blood platelet aggregation, or antiallergic. PREPARATION:For example, a compound shown by the formula II is halogenated to give a corresponding compound shown by the formula I (formula III).

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides pharmacological activities, particularly cardiotonic effects, antihypertensive effects, and cerebrovascular effects.
Circulatory system effects such as diastolic effect and platelet aggregation inhibiting effect
A new nagelimidi with antiallergenic and/or antiallergic effects
derivatives, their production methods and pharmaceutical compositions containing them
It is related to. More specifically, the present invention relates to the formula [wherein R1 is a hydrogen atom, optionally lower alkoxy, lower
Alkyno halogen and/or lower alkylthio
means an aryl group or a bare cyclic group which may be substituted with
), R2 is a group represented by the formula % (wherein R is optionally lower alkyl, lower alkokene,
Optionally substituted with amino and/or acylamino
aryl group, Rb is a hydrogen atom or lower alkyl group,
Formula -N is optionally acyl and/or alkyl (lower
) N-containing heterocyclic group optionally substituted with alkyl
R3 is a hydrogen atom, a lower alkyl group, or a bond thereof.
If the N atom is trivalent in the absence of R, then R exists.
and R4 is 8) optionally lower alkyl, aryl or alk(
(lower) alkyl-substituted imino group, or
b) Lower alkyl group, hydrogen atom, halogen, lower alkyl group
Kylthio group, optionally lower alkyl, aryl, al (lower
class) even if substituted with alkyl and/or acyl
Good amine groups, optionally acyl and/or al (lower
) N-containing heterocyclic group optionally substituted with alkyl
), R5 is a hydrogen atom; lower alkyl group, optionally lower alkyl
Lower alkanoyl group optionally substituted with amino or
or the bonded N atom is trivalent without R5
In some cases, R5 is absent, or R3 and R4, or R4 and R5 are adjacent back atoms or
and a nitrogen atom to form an N-containing heterocyclic group.
R6 may be a hydrogen atom, a lower alkyl group, a halogen or any
lower alkoxy, lower alkyl, halogen and/or
or lower alkylthio.
The group 222 represents a single bond or a double bond, and
222 represents 1.2 or 3 double bonds, respectively.
vinegar. However, R1 and R6 are not hydrogen atoms at the same time] Hyrimidine derivatives and salts thereof, and
, its manufacturing method, and pharmaceutical compositions containing it.
It is. For the target compound of the present invention [11, R3 and/or
or when R5 is a hydrogen atom, the target compound [I]
The rimidine ring can also be represented by its tautomers.
Ru. That is, R and R5 are both hydrogen, and R4 is lower
When it is an alkyl group and R2 is =N-R2,
Compound [1] has one of the structural formulas (A) to (C) as shown below.
It can be expressed as (lower alkyl) (lower alkyl) (lower alkyl) (
In the formula, R1, R2 and R6 each have the same meaning as before)
. The target compound can be expressed in any of these tautomeric forms.
Alternatively, the target compounds may coexist as an equilibrium mixture.
Good too. All of these tautomers are within the scope of this invention.
included in. The object compounds [1] of this invention and their salts are as follows:
It can be manufactured by the manufacturing method described below. Production method 1 (halogenation)
)E engineering a] (Ibl manufacturing method 3 [engineering a] (engineering C) manufacturing
Method 4 (acylation) [Idl [Glaze] Production method 5 (ring closure)
) [F] [Pg] Manufacturing
Method 6 [Work al (Work h) Manufacturing method 7 [Work il (Work j]
[V month [VIX] [Il Main production method 10 (N-alkylation) [Eng kl (January production method 11 (reduction)
original) [engineering m] [engineering n1 manufacturing method
12 (Acylation) [IO] [Engineering p] Manufacturing method
13 (Acylation) [In the formula, R1, R2, R3, R4, R5, R6, R2 or
and 222 bond and 2 in ring A each have the same as before.
X and X2 are each halogen, R2 is a lower alkyl group, R2 is substituted with a hyalazin-1-yl group, or an amine
arylamino group, R2 is an acyl-substituted piperazin-1-yl group, or
or an arylamino group substituted with acylamino, R4 is a lower alkylthio group or optionally lower alkyl,
Aryl, al(lower)alkyl and/or acyl
an optionally substituted amino group, a group, or optionally
a hydrazino group optionally substituted with acyl, R4 is one
R4 is a lacin-1-yl group, a hydrazino group or an amino group, R4 is an acyl-substituted piperazin-1-yl group, an acyl-substituted piperazin-1-yl group,
a hydrazino group or an acylamino group substituted with sil, R5 is a lower alkyl group, R may be optionally substituted with lower alkylamino
lower alkanoyl group, R7 is lower alkyl group, R8 is lower alkyl group, aryl group or Al (lower)
an alkyl group, and Y means a leaving group. Definitions of various substituents used in this specification
Description and preferred examples thereof will be described in detail below. “Lower” means 1 to 6 carbon atoms, unless otherwise specified.
shall mean. Suitable examples of "lower alkyl groups" include methyl, ethyl
ru, zorol, isopropyl, butyl, isobutyl,
Straight chain still like tertiary butyl, pentyl, hexyl etc.
is a branched alkyl group. Suitable examples of "aryl group" include phenyl, naphthi
and biphenylyl. Aryl groups of R1 and R6 are, for example, methoxy, ethoxy,
Oxy, propoxy, impropoxy, butoxy, tertiary
Lower atom acids such as butoxy, intyloxy, hexyloxy, etc.
alkoxy groups, lower alkyl groups as mentioned above, e.g.
chlorine, halogens such as bromine and iodine, and
For example, methylthio, ethylthio, propylthio, isopropylthio,
From lower alkylthio groups such as lopylthio and hexylthio
Such compounds may have 1 to 4 selected substituents.
Preferred examples of aryl groups having such substituents include:
For example, 4-methoxyphenyl, 3,4-dimethoxyphene
Nyl, 3,4.5-trimethoxyphenyl, 2,3.4
-1rimethoxyphenyl, 2-ethoxyphenyl, 4-
Lower alkoxy-substituted aryls such as hexyloxyphenyl
groups such as p-tolyl, m-tolyl, 0-tolyl, 4
-Ethylphenyl 4-hexylphenyl, 2.6-
dimethylphenyl, 3,4-dimethylphenyl, 2゜4
．． Lower alkyl substituted aryls such as 6-drimethylphenyl
group, such as 2-methyl-4-methoxyphenyl, 2-
Ethyl-4-methoxyphenyl, 3-ethyl-4-eth
Lower alkoxy and lower alkyl groups such as xyphenyl
substituted aryl groups, such as 4-fluorophenyl, 3-fluor
Orophenyl, 4-chlorophenyl, 4-bromophenyl
, 4-iodophenyl, 3,4-difluorophenyl
halogenated aryl groups such as 4-methylthiophene
Nyl, 4-ethylthiophenyl, 2-propylthiophenyl
lower alkyl groups such as phenyl, 4-hexylthiophenyl, etc.
O-substituted aryl groups, such as 3-medoxy-4-methylthi
ophenyl, 4-methoxy-2-methylthiophenyl,
3-methoxy-4-ethylthiophenyl, 2-ethoxy
Lower alkylthio and
and lower alkoxy-substituted aryl groups. The aryl group of R2 is a lower alkyl group or a lower alkoxy group
, amino groups and/or e.g. mesylamine, ethane
Sulfonylamine, isobutanesulfonylamino, etc.
Acylamino groups such as alkanesulfonylamino groups
may be replaced with . R having such a substituent
As a preferable example of the aryl group of 2, the aryl group of R and R6 is
In addition to the groups exemplified above for the lyl group, 3-
Aminophenyl, 4-aminophenyl, 3-mesylami
Nophenyl, 4-mesylaminophenyl, 4-ethane
Examples include sulfonylaminophenyl. Preference for R2 “arylamino group substituted with amino group”
Suitable examples include 4-aminoanilino, 3-aminoanilino
Examples include Reno et al. R2 “Arylamino group substituted with acylamino group
Suitable examples of ``2-mesylaminoanilino, 4
-Mesylaminoanilino, 4-ethanesulfonylamino
Anilino, 4-isopropanesulfonylaminoanilino
etc. A suitable example of "al(lower) alkyl group" is
Zyl, buenethyl, 3-phenylpro. Examples include ru, penzhydrino, trityl, etc. Suitable examples of "N-containing heterocyclic group" include, for example,
gerolyl, -lolinyl, imidazolyl, hyolazolyl,
Viridi L, 1,2,3,6-titrahydrolysyl,
1,2-dihydro pyrimidinyl, hi0ra
Dinyl, -ridazinyl, triazolyl, tetrazolyl, etc.
unsaturated 5- or 6-membered complex monomer containing 1 to 4 nitrogen atoms
Cyclic group; for example, pyrrolidinyl, imidazolidinyl
1 to 4 nitrogen atoms such as pizzeridinyl, 2 yazinyl, etc.
a saturated 5- or 6-membered heteromonocyclic group containing; e.g.
Lino murmur isoindolyl, indolinyl, 1 benzimida
Nitrogen atom 1 in zolyl, quinolyl, benzotriazolyl, etc.
Examples include unsaturated fused heterocyclic groups containing ~5 groups. For example, a 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms.
Examples include 4-pyridyl, 3-pyridino
L-, 1.2.3.6-titrahydrolysine-1-
An example of this is the stop. Heterocyclic groups include, for example, formyl, acetyl, propionyl,
4. Lower alkanoyl groups such as valeryl, -valoyl, e.g.
For example, mesyl, ethanesulfonyl, isobutanesulfonyl
lower alkanesulfonyl groups such as benzoyl,
p-Toluoyl, 4-fluorobenzoyl, 4-chloro
Benzoyl, 2,4-difluorobenzoyl, 4-chloro
lo-3-sulfamoylbenzoyl, 4-trifluoro
Methyl-3-sulfamoylbenzoyl, 2,4-cyc
0-5-sulfamoylbenzoyl, etc., optionally halo
Gen, sulfamoyl, lower alkyl and lower alkali
Substituted with an appropriate substituent selected from sulfonylamino
Acyl groups such as aroyl groups, which may be
/ or benzino murmur 2-fenechino murmur 2-phenilde
Al (lower) als such as rohilol, benzhydryl, etc.
It may be substituted with a kill group. N-containing in acyl and/or alkyl
Preferred examples of heterocyclic groups include 4-formyl h6
r Razin-1-Ino murmur 4-acetylhi0zeRazine-1
-yl, 4-penzoylhydrazin-1-yl, 4-
(4-fluorobenzoyl)-zeracin-1-yl, 1
-acetylimidazolidin-2-yl, 4-(2,4-
dichloro-5-sulfamoylbenzoyl)hyserazine
-1-yl, 4-(4-trifluoromethyl-3-sul)
famoylbenzoyl) bizerazine-air, 4-pe
Njiru-Serazine-1-Ino-Mutsu-4-Benzhydrylbize
Radin-1-yl, 4-(2-chloro-4-benzhyde
lyl-5-sulfamoyl) pizeradin-1-yl, etc.
Can be mentioned. R3 and R4, or R4 and R5 together, are adjacent
The above-mentioned carbon atoms and nitrogen atoms are bonded to
N-containing heterocyclic groups may also be formed. R2 and R4 are substituted with acyl
C din-1-yl group is substituted with an acyl group as exemplified above.
a substituted piperazin-1-yl group, a preferred example thereof
is 4-formyl bi-coated di-1-yl, 4-acetyl bi
trannn-1-ino murmur 4-hensoilbizerajin-1
-yl, 4-(2,4-sochloro~5-sulfamoyl
benzoyl)hyceracin-1-yl, j-(4-trif)
fluoromethyl-3-sulfamoylbenzoyl)hihara
Syn-1-inob, 4-(4-fluorobenzoyl)hydrogen
/glazin-1-yl, etc. Suitable acylamino groups include, for example, mesylamino
, ethanesulfonylamino, propanesulfonylamino
, iso4-thanesulfonylamino, butanesulfonylamino
Lower alkanesulfonylamino groups such as mino etc.
It will be done. The imino group of R4 is a lower alkyl group or an aryl group as described above.
Substituted with an alkyl group or an alkyl group (lower)
Suitable examples of imino groups having such substituents and
For example, methylimino, ethylimino, hexyl
Lower alkyl substituted imino groups such as imino, e.g. phenyl
Aryl-substituted imino groups such as imino, naphthylimino, etc., e.g.
For example, hensylimino, phenethylimino, benzhydrimino
Al(lower)alkyl-substituted imino groups such as lumino etc.
can be lost. Suitable examples of "1 halogen" include chlorine, bromine, iodine and
and fluorine. A suitable example of "lower alkylthio group" is methylthio group.
Ethylthio, ethylthio, isopropylthio,
Examples include butylthio, 4-methylthio, hexylthio, etc.
Ru. The amino groups of R4 and R4 are lower alkyl groups, aryl groups,
Al group, Al(lower)alkyl group and/or Acyl group
may be substituted with
Suitable examples of the amine group include, for example, methylamino, ethyl
Ruamino, propylamine, inpropylamino, hexa
Cylamino, dimethylamino, diethylamino, dife
Nylamino, N-ethyl-N-methylamino, N-methylamino
Lower alkyl substituted amine groups such as -N-propylamine
, e.g. anilino, diphenylamino, naphthylamino
aryl-substituted amine groups such as benzylamino, fluorine, etc.
penethylamino, tritylamino, henthylamino, etc.
an alk(lower)alkyl-substituted amine group, e.g.
Lower alkyl such as luanilino, N-ethylanilino
and aryl-substituted amine 7 groups, such as N-benzyl-N-methane.
Thylamine, N-phenethyl-N-methylamino, etc.
alkyl and al(lower)alkyl-substituted amino groups
and lower alkanesulfonylamino groups as mentioned above.
can be lost. The hydrazino groups of R, R, and Ro are
It may be substituted with a sil group. A preferred example of a hydrazino group substituted with an acyl group is
For example, 2-formyl hydrazino, 2-acetyl hydrazino
radino, 2-propionylhydrazino, 2-be〉di
Ruhydrazino, 2-'(4-fluorobenzoyl)hydro
Examples include radino and the like. Suitable examples of "lower alkanoyl group" include, for example,
Formyl, acetinoproonil, valeryl, Hi0ba
Royle et al. The "lower alkanoyl group" of R and Rb is methylaminoyl group.
ethylamino, 1-ethylamine, propylamino
, substituted with lower alkylamino groups such as butylamino, etc.
may have been done. "Lower alkanoyl group substituted with lower alkylamino"
Preferred examples of ``methylaminoacetyl, methyl
Examples include lucarbamoyl and ethylcarbamoyl. Suitable examples of the leaving group represented by Y include, for example, chlorine
, toherogens such as bromine and iodine, e.g. benzene
Sulfonate, p-toluenesulfonate, methanesulfonate
Examples include sulfonates such as phonate. 2 in ring A is 1.2 or 3 double bonds in ring A
This means that there is a ring A of this type.
gin, 3,4-dihydro rimidine, 1,2.3.4
-tetrahydro rimidine and the like. Kirani details
Specifically, the pyrimidine derivative [1] of the present invention includes:
Compounds represented by the following structural formulas, their salts and their
These tautomers are included. [Nee IJ [Nee 21 [Nee 31 [Nee 41 R'] [Nee 51 [Aero 1 As a salt of the target compound [I], it is a pharmaceutically acceptable salt.
Includes customary non-toxic salts, such as formates, acetates, and
Lifluoroacetate, maleate, tartrate, methane
Sulfonate, Benzene Sulfonate, Toluene Sulfone
Organic acid salts such as hydrochlorides, odorous hydrogen salts, sulfur
Inorganic acid salts such as acid salts and phosphates, e.g. arginine salts, glucose
Examples include salts with amino acids such as tamates and ornithine salts.
can be lost. In addition, the salts of compounds [Ia] to [Ir] are
This includes the same things listed above. The method for producing the target compound [I] and its salts will be explained in detail below.
I will clarify. Production method 1 Target compound [I a] and its salt are compound [1[]
or manufactured by halogenating its salt.
I can do it. Suitable salts for compound [1] include
The same examples as those mentioned above can be mentioned. Suitable halogenating agents used in this production method include:
For example, oxyhalogens such as oxysmell north neighbor, phosphorus oxychloride, etc.
North neighbor, such as five odor north neighbor, trichloride ditch, five fu north neighbor, etc.
North neighbor Rogen, such as Sanshu north neighbor, Sanchloridou, Wangfu north neighbor, etc.
The trihalogen to the north of, e.g. thionyl chloride, thionyl bromide
thionyl halides such as triphenylphosphine
dichloride, triphenylphosphine, tools (first class)
Triphenylphosphine dihalide! 'like
Examples include commonly used ones. This reaction is usually performed using methylene chloride, chloroformo 1,tetrasalt
Carbonated carbon, benzene, tetrahydrofuran, dimethylform
in conventional solvents such as Muamide, dimethyl sulfoxide.
However, as long as the solvent does not adversely affect the reaction.
The reaction can be carried out in any other organic solvent.
Ru. If the halogenating agent is a liquid, it can be used as a solvent.
It can also be used as The reaction temperature is not particularly limited, and the reaction may be performed under cooling or heating.
It can be performed. Production method 2 - Target compound [1b] and its salt are compound [I a]
or can be produced by reducing its salt.
Ru. The reaction can be carried out in conventional manner, i.e. by chemical or catalytic reduction.
You can do this. Suitable reducing agents used for chemical reduction are e.g.
Lithium aluminum, sodium aluminum hydride
, aluminum hydride, trimethoxyaluminum hydride
Mulithium, tri-tert-butoxyaluminum hydride
Aluminum hydride compounds such as lithium, e.g.
Riphenylsus, tributyltin hydride, dibutyltin hydride
Tin hydride compounds such as rutin, sodium borohydride
, metal hydride compounds such as aluminum borohydride, etc.
substances; for example, alkalis such as lithium, sodium, potassium, etc.
Metals such as methanol, ethanol, tertiary butyl
Combinations with alcohol such as alcohol, e.g.
Alkaline earth metals such as sium and calcium and methane
With alcohol such as ethanol and amyl alcohol
Combinations of: zinc and e.g. acetic acid, propionic acid, hydrochloric acid, etc.
combination with acid, etc. Suitable catalysts used for catalytic reduction are, for example, platinum plates, white
Gold sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
Platinum catalyst 2 e.g. palladium sponge, palladium black, oxidized
Palladium, /-0 radium-carbon, colloidal radium
Umu, noguraji'7mu6 [valium, 71°u, jiu
/f radium catalysts such as barium carbonate, e.g.
Nickel contacts such as nickel, butyride, and Raney nickel
cobalt, such as reduced cobalt, Raney cobalt, etc.
Catalysts, e.g. reduced iron, iron catalysts such as Raney iron, e.g. reduced
Commonly used copper catalysts such as steel, Raney copper, Ullmann copper etc.
It is a catalyst. The reduction in this process is usually carried out using water, e.g.
Alcono such as Tanol, Furo/Gunor, etc.
-TeL, dioxane, tetrahydrofuran, acetic acid, pro-
It is carried out in conventional solvents such as pionic acid and the like. these
The solvent depends on the type of reduction method used in this manufacturing method and the reducing agent used.
Selected depending on type or type of catalyst. The reaction temperature is not particularly limited, and reaction may be performed under cooling or heating.
response. Production method 3 Target compound [I c] and its salt are compound [1a]
or its salt reacted with compound [1[[] or its salt.
It can be manufactured by Suitable salts of compound [I[[] include lower alkanes.
Excluding the case of thiol, the examples given for compound [1]
The same salts as thiol compounds [1[[]
Suitable salts include, for example, lithium salt, sodium salt,
Inorganic salts, potassium salts, calcium salts, norium salts, etc.
Base salts, ammonium salts, such as hyricine salts, torie
Common base additions such as organic base salts such as thylamine salts, etc.
Salt is an example. This reaction is performed, for example, with sodium hydride, potassium hydride
alkali metal hydrides such as calcium hydride,
Alkaline earth metal hydrides such as magnesium hydride, e.g.
Alkali metals such as sodium hydroxide and potassium hydroxide
Hydroxides, such as sodium carbonate, potassium carbonate, carbonic acid
Alkali metal carbon such as sodium hydrogen and potassium hydrogen carbonate
in the presence of an inorganic base such as an acid salt or a bicarbonate.
Uno is preferable. The reaction usually involves water, methanol, ethanol, and
Nol, dioxane, tetrahydrofuran, dimethyl fluoride
Common uses like lumamide, methylene chloride, chloroform
The reaction is carried out in a solvent that does not adversely affect the reaction.
If so, the reaction can be carried out in any other organic solvent.
I can do that. The reaction temperature is not particularly limited, and the reaction may be performed under cooling or heating.
It can be performed. Production method 4 Target compound [1e] and its salt are compound [Id] or
or by acylating its salt.
Wear. A suitable example of the acylating agent used in this production method is
, lower alkyl acids such as formic acid, acetic acid, propionic acid, valeric acid, etc.
lucanoic acid, e.g. benzoic acid, naphthoic acid, 4-fluoro
Benzoic acid, 4-chlorobenzoic acid, 4-chloro-3-
Sulfamoylbenzoic acid, 2,4-dichloro-5-sul
Famoylbenzoic acid arylcarboxylic acid, lower alkali
Organic acids such as sulfonic acid, e.g. methyl isocyanate
Isocyanates such as ethyl isocyanate, ethyl isocyanate, etc.
salts of acids or their in carboxy or sulfo groups;
Examples include reactive derivatives. Suitable salts of acids include 2, for example sodium salts, potassium salts,
Inorganic base salts such as aluminum salts, calcium salts, magnesium salts,
For example, trimethylamine salt, triethylamine salt, pyrylamine salt,
Salts with conventional bases such as organic base salts such as gin salts are mentioned.
can be lost. Preference for reactive derivatives at carboxy or sulfo groups
Suitable examples include butychlorides, acid bromides, sulfur chlorides, etc.
Acid halides such as honyl and sulfonyl bromide; symmetrical acid-free
Water; for example, aliphatic carboxylic acids such as acetic acid and hybaric acid
, for example, dialkyl phosphoric acid, diphenyl phosphoric acid, etc.
mixed acid anhydrides with acids such as phosphoric acid; e.g.
ester, ethyl ester, propyl ester, hexyl ester
Lower alkyl esters such as ster, e.g. benzyl esters
ester, benzhydryl ester, P-chlorobenzyl ester
Substituted or unsubstituted alk(lower) alkyl such as ster
esters, such as phenyl esters, tolyl esters
, 4-nitrophenyle7ter, 2,4-dinitrophe
Nyl ester, tantachlorophenyl ester, naphthi
substituted or unsubstituted aryl esters, such as
or N,N-dimethylhydroxylamine, N-
Hydroxysuccinimide, N-hydroxyphthalyl
mido or 1-hydroxy-6-chloro-IH-benzo
Examples include esters such as those with triazoles.
It will be done. This reaction is typically performed using water, methanol, ethanol, or propane.
No-jL, tetralin, tetrahydrofuran, dioxa
chloroform, toluene, dimethylformamide,
carried out in a conventional solvent such as dimethyl sulfoxide
However, other solvents may be used as long as they do not adversely affect the reaction.
The reaction can be carried out in any organic solvent. This reaction can be carried out using an inorganic base as exemplified in Production Method 3 or
Contains lymethylamine, triethylamine, lysine, etc.
Preferably carried out in the presence of a conventional base such as a base.
. If the acylating agent is used in the form of the free acid or its salts,
For example, N,N/-dicyclohexyl carbodi
The presence of a conventional condensing agent such as an imide is preferred.
. The reaction temperature is not particularly limited, and the reaction may be performed under cooling or heating.
It can be performed. Production method 5 Target compound [1g] and its salt are compound [I f]
or can be produced by ring-closing its salt.
Ru. This reaction involves water, methanol, ethanol-4, and zolopanol.
, tetralin, tetrahydrofuran, dioxane, chloro
loform, toluene, dimethylformamide, dimethyl
in the presence or presence of conventional solvents such as sulfoxides
Solvents that do not adversely affect the reaction are used without
(2) It can also be carried out in any other organic solvent.
can. This reaction can be carried out, for example, by formic acid, acetic acid, benzenesulfone fi,
Organics such as P-1-luenesulfonic acid and trifluoroacetic acid
Acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., non-acids, e.g.
Cation exchange resins such as sulfonate/noristyrene resins
It is preferable to carry out the reaction in the presence of an acid such as (acid type). This reaction can also be performed by azeotropic dehydration, such as dehydration in the presence of a dehydrating agent, etc.
Preferably it is carried out under aqueous conditions. Suitable examples of dehydrating agents include polyphosphoric acid, prephosphoric acid, etc.
Ester, phosphorus oxychloride, oxy-odor north neighbor, pentaacid north neighbor, etc.
Phosphorus compounds, such as acid anhydrides such as acetic anhydride and benzoic anhydride
etc. The reaction temperature is not particularly limited, but is usually room temperature or heated
The reaction is carried out under heat or under heat. ” Sumitaka J The target compound [I h] and its salt are the compound [I a
] or its salt is reacted with compound [IV] or its salt.
It can be manufactured by Suitable salts of compound [IV] include, for example, lithium
salt, sodium salt, potassium salt, calcium salt, barium
Inorganic base salts such as ammonium salts, ammonium salts, e.g. pyridine
Commonly used salts, such as organic base salts such as triethylamine salts, etc.
Examples include base addition salts of. That is, compound [IV]
and preferable examples of its salts include hydrogen azide, azide
Hydrogen acid, sodium azide, potassium azide, lithium azide
tium, calcium azide, barium azide, azide
Examples include ammonium and the like. This reaction typically involves water, methanol, ethanol, and dioxyl.
San, N, N-dimethylformamide, methyl cellosol
does not adversely affect reactions like ethyl cellosolve.
in a conventional solvent or in a mixture thereof. The reaction temperature is not particularly limited, but is usually room temperature or heated
The reaction is carried out under heat or under heat. The target compound [I j] and its salt are the compound [I i
] or its salt as compound [V], that is, an alkylating agent.
It can be produced by reacting with. Suitable examples of the alkylating agent [V] include, for example, iodide
ethyl iodide, methyl bromine, methyl chloride, ethyl iodide, ethyl bromide
Low levels of propyl iodide, butylene hexyl iodide, etc.
class alkyl halides, e.g. if, -)
Methyl sulfonate, ethyl p-toluenesulfonate, p-
Hexyl toluenesulfonate, Methyl henzenesulfonate
lower alkaline acids of sulfonic acids such as methyl methanesulfonate,
Among these, kill esters are most suitable.
are lower alkyl iodides, the most preferred are
It is methyl iodide. This reaction is carried out by, for example, sodium hydride, potassium hydride, etc.
alkali metal hydrides, e.g. calcium hydride, water
Alkaline earth metal hydrides such as chlorinated magnesium, e.g.
Alkali metal water such as sodium hydroxide and potassium hydroxide
oxides, e.g. bicarbonates, e.g. sodium methoxy
Sodium ethoxyde, potassium tertiary butoxide, etc.
Alkali metal alkoxides such as alkali metal alkoxides of
In the presence of a base such as a sid or in the absence of a base.
It will be done. This reaction is usually performed using methanol, ethanol, or
alcohol, tetrahydrofuran, dioxane, methylene chloride
, chloroform, dimethylformamide, dimethylsulfate
Use conventional solvents that do not adversely affect the reaction, such as phoxide, etc.
It is done in medium. The reaction temperature is not particularly limited, and the reaction may be performed under cooling or heating.
It can be performed. In this production method, the pyrimidine ring of compound [Ii]
The nitrogen atom at the -position of is alkylated, as indicated by R7
groups are simultaneously removed in this reaction. Production method 8 Target compound [I] and its salt are compound [VI] or
is a reaction for introducing an amino group or an aryloxy group into the salt.
It can be manufactured by subjecting it to. Suitable salts for compound [VI] include compound [1]
The same salts as those exemplified above can be mentioned. This reaction converts chemical food [VI] or its salt into R2 group
Amine compounds or phenolic compounds containing i.e.
, by reacting with a compound of the formula R2-H
be able to. The reaction is carried out in the presence of a conventional organic or inorganic base.
Good too. The reaction is usually methanol, ethanol, dioxane, salt
Use conventional solvents that do not adversely affect the reaction, such as methylene chloride.
It is done in medium. When the amino compound is a liquid,
It can also be used as a solvent. The reaction temperature is not particularly limited, and the reaction may be performed under cooling or heating.
It can be performed. Production method 9 Compound [11 and its salts are compound [■] or its salts.
Subjecting the salt to an amine group or aryloxy group introduction reaction
It can be manufactured by Suitable salts of compound [■] include compound [1].
The same salts as those exemplified above can be mentioned. This introduction reaction converts the oxo group at the fourth position into a thioxo group or
convert it into a logeno group, and then convert the resulting compound into R2, etc.
Reacts with amino compounds or phenolic compounds containing groups such as
This can be done by forcing. Conversion of oxo group to thioxo group or halogeno group is
Example of compound [■] or its salt in three-value north neighbor or manufacturing method 1
This can be done by reacting with the halogenating agent shown.
can. Thioxo compounds or halogen compounds produced
The reaction between and amino or phenolic compounds is
It can be carried out qualitatively in the same manner as Production Method 8. Production method 10 The target compound [I N] and its salt are the compound [Ik
] or by reacting its salt with an alkylating agent.
can be manufactured. The reaction in this production method is carried out substantially in the same manner as in Production Method 7.
be able to. Production method 11 Compound [I n] and its salt can be prepared from compound [1m] or
can be produced by reducing its salt. The reaction can be carried out substantially in the same manner as Production Method 2.
. Production method 12 Compound CI pco and its salt can be prepared from compound [1 ol or
can be produced by acylating its salt.
Ru. The reaction can be carried out substantially in the same manner as Production Method 4.
. Compound [Iol or its salt as lower alkyl isocyanate]
When reacting with a lower alkyl carbamate, R5 is
A compound [1p] having a moyl group is obtained. The compound [I rl and its salts are the compound [I q] or
or by acylating its salt.
Wear. The reaction can be carried out substantially in the same manner as Production Method 4.
. Target compound [1g] to [I rl obtained by the above production method
is extracted from the reaction mixture, recrystallized, and column chromatographed.
Separation and FMH can be carried out by conventional methods such as fee etc.
can. Target compounds [I a] to [Irl are obtained in free form
Optionally, these can be converted into the above salts by conventional methods.
You can Among the starting materials for the above production method, the starting material compound is new.
European Patent Application Box 84'301741
．． By the method described in No. 9 (Publication No. 0123402)
can be manufactured. Furthermore, the starting material [Vl]
and certain starting materials [■] are also new compounds.
By the following manufacturing method or the manufacturing examples illustrated later.
and can be manufactured in the same manner as in the examples. Production method A [From V-technique] or its reactive derivative at the carboxy group Production method B (N-alkylation) [V-ed] [V-technique]
Reactive derivative 1 in a] (halogenation) [V engineering] [v engineering] - Production method E Ammonia [XI] [X1 month [
Vee] (wherein, R1, R3, R4, R5, R6, X2 and
22 bond and 22 in ring A each have the same meaning as before.
Yes; R3 is a lower alkyl group; R4 is a lower alkyl group; R4 is hydrogen or a lower alkyl group; R and R10 each mean a lower alkyl group)
. The manufacturing method of the raw material compounds and their salts will be explained in detail below.
Ru. Production method A Compound [■b] and its salt are compound [IX] or
its reactive derivative or its salt at the carboxy group
Manufactured by reacting with a compound [■
can do. Suitable salts of compounds [■b], [■co and [IX]
The same salts as those exemplified for compound [I]
can be mentioned. Suitable reactive inducer in the carboxy group of compound [IX]
As a conductor, ester, acid halide, acid anhydride
etc. These reactive derivatives should be used
Can be arbitrarily selected depending on the type of compound [IX]
Ru. The reaction is usually carried out using water, methanol, ethanol,
tetralin, tetrahydrofuran, dioxane,
Chloroform, toluene, dimethylformamide, dimethyl
carried out in a conventional solvent such as tylsulfoxide,
Any other solvent may be used as long as it does not adversely affect the reaction.
The reaction can also be carried out in organic solvents. This reaction is carried out using inorganic acids such as hydrochloric acid, sulfuric acid, polyphosphoric acid, etc.
For example, trifluoroacetic acid, benzenesulfonic acid, toluene
Performing in the presence of acids such as organic acids such as sulfonic acids
is preferred. The reaction can also be performed by azeotropic dehydration, e.g. magnesium sulfate, anhydrous salt
Such as zinc oxide, pentoxide groove, zeolite, silica gel etc.
It can also be carried out under dehydrating conditions, such as in the presence of a dehydrating agent.
Ru. When compound [IV] is used in the form of free acid or salt
In this case, the reaction is preferably carried out in the presence of customary condensing agents. The reaction temperature is not particularly limited, and is usually room temperature or heated.
or the reaction is carried out under heating. Production method B Compound [■a] and its salt can be prepared by compound [■d] or
is produced by reacting its salt with an alkylating agent.
can be done. Suitable salts of compounds [■a] and [■d] include:
The same salts as those exemplified for compound [I] are listed.
It will be done. The reaction can be carried out substantially in the same manner as Production Method 7.
. Therefore, the alkylating agent and reaction conditions are as described in Process 7.
Please refer to . Production method C Compound [■C] and its salt are compound [IX] or
its reactive derivatives in the carboxy group or its towers
, produced by reacting with compound [X] or a salt thereof
can be built. Suitable salts of compounds [■C1, [IX] and [X] and
The same salts as those exemplified for compound [1]
can be mentioned. The reaction can be carried out substantially in the same manner as Production Method A.
. Therefore, the description can be referred to for the reaction conditions. Manufacturing method Compound [■Co or its salts]
It can be produced by halogenating a salt. Suitable salts of compounds [VI] and [■] include
The same salts as those exemplified for compound [I] can be mentioned.
Ru. The reaction can be carried out substantially in the same manner as Production Method 1.
. Therefore, for the reaction conditions, refer to the explanation. Production method E 1) Compound [XII] and its salt are compound [XI]
can be produced by reacting with ammonia.
Wear. Suitable salts of compound [XII] include compound [I]
Examples include the same salts as those listed above. The reaction is usually carried out in a solvent such as water, ethanol, or
in any other solvent that does not adversely affect the
Alternatively, it may be carried out under cooling, at room temperature, or under heating. 2 compound 417 [■e] and its salt were obtained above.
Compound [XII] or a salt thereof is converted into compound [XIII]
Obtained by reacting with Suitable salts for compound [■e] include compound [1]
The same salts as those exemplified above can be mentioned. The reaction may be carried out in the presence of conventional organic or inorganic acids.
stomach. The reaction is usually carried out in a solvent such as ethanol or
in any other non-affecting solvent, preferably
It is carried out at room temperature, under heat or under heat. Target compound [I] and starting materials [I], [■co and
Certain types of [V] to [XIII] have an inorganic residue in the molecule.
based on asymmetric carbon atoms and/or carbon-nitrogen double bonds
stereoisomers, and all such isomers are
shall be included within the scope of this specification. ? In order to demonstrate the pharmacological activity of rimidine derivative [I], cardiotonic
The activity test results are shown below. Test method A (cardiotropic activity) Male mosquito mongrel dogs were treated with 35 mg of sodium barbicure.
Anesthetized by intraperitoneal injection of /kg. let animals breathe naturally
I set it. The tissue artery is isolated and filled with heparinized saline.
Insert the filled catheter (USCI, 18 F),
The patient was advanced to the left ventricle. Catheter with pressure transducer (Nihon Kohdensha)
(manufactured by MPU-0, 5A) to measure left ventricular pressure.
, from the measured value, calculate the dp/dt maximum value using an analog controller.
Guided by a motor. Insert a cannula into the left femoral artery to measure systemic blood pressure
did. Blood pressure pulse was used to trigger the heart rate monitor. of drugs
For injection, place another catheter through the right femoral vein.
It was located inside the cave. Systemic blood pressure, left ventricular pressure, dp/dt maximum value, and heart rate are displayed.
Same as Regram (manufactured by Nihon Kohden, RJ G-4008)
The time was recorded. Test compounds were added to distilled water (0.2 ml/kg) or diluted with
Dissolved in methyl sulfoxide (0.04 ml/kg)
and injected into the femoral vein. Administer post-administration parameters
Compared with the previous parameters. The test results were calculated using the following formula: dp/dt maximum dog value change (dp
/dt M, C,) expressed as a percentage. The conclusion *3
-amino-5-(4-pyridyl)-2(IH11')-
Hydrolysinone: A well-known drug that has actually been used as a cardiotonic drug.
Compound. Examination 1 (antiplatelet activity) Platelet abundance containing 6.5 to 7.5 x 1♂ platelets/ml
Plasma enriched (PRP) was prepared from rabbit blood. P RP 200μm, calcium chloride (1mM) 5
μl, and containing 120mM NaCl and test compound.
Lis acetate solution (5mM) at pH 7.4
0 μm were added sequentially and then stirred at 37° C. for 2 minutes. Add adenosine diphosphate (ADP) (2
, 5 μM) 5 μm or collagen (25 μg/ml)
5 μm was added as an aggregation inducer. Agglutinometer (Nihon Kohdensha)
Aggregation was measured using Hematracer 1). ■D5
o is shown in Table 2. Test results B Table 2 Test method C (antihypertensive activity) A single nephrectomy was performed under anesthesia from a 5-year-old Wistar male rat.
Ta. Deoxycorticosterone acetate (DOCA)
Suspended in peanut oil (30mg/kg) twice a week
Subcutaneous injection and 1% saline was given instead of drinking water. average
5 to 7 days after single nephrectomy in animals with blood pressure of 150 to 200 mmHg.
Used for experiments for a week. Test compounds were administered orally. Femoral motion using a pressure transducer
Blood pressure was measured by pulse and mean arterial pressure was recorded. Test result C The average ratio of maximum drop in blood pressure (mmHg) is shown in Table 3.
. Table 3 As is clear from the above test and results, the purpose of this invention is
Compound [I] is a cardiotonic drug, antihypertensive drug, cerebral vasodilator and
It is useful as a platelet aggregation inhibitor. The object compound [1] of this invention and pharmaceuticals for treatment
The salts thereof are acceptable for oral administration, parenteral administration or
is an organic or inorganic solid or liquid form suitable for external use.
mixed with a conventional pharmaceutically acceptable phase such as
, used in the form of conventional pharmaceutical preparations. Pharmaceutical preparations are covered
solid compositions such as tablets, dragees or tablets;
may also be used as a solution, suspension or emulsion.
It may also be a liquid composition such as. Above if necessary
In the formulation, auxiliaries, stabilizers, wetting agents or emulsifiers, buffers
Contains any other commonly used additives
good. Cardiotropes, antihypertensives, cerebral vasodilators, platelet aggregation inhibitors
Or, the pharmaceutical composition of an antiallergic drug is a compound CI] or an antiallergic drug.
Or its salt is usually used as an active ingredient at 0.01 m/day.
g/kg ~500mg/kg for 1 to 4 doses
administered. However, this dose may vary depending on the patient's age,
May be increased or decreased depending on body weight, conditions, and administration method
. Hereinafter, this invention will be explained in detail according to production examples and examples.
Explain in detail. Production example 1 Acetamidine hydrochloride (28.11g) in methanol
(200 ml) solution, add sodium methoxide (17
, 7g) and stirred at room temperature for 10 minutes. This suspension
The solvent was distilled off and ethanol (200ml) was added.
Ru. This suspension was added to veratroyl ethyl acetate (50,0
Add a toluene (300ml) solution of g) and bring the temperature to 1.
The solvent is distilled off until 10°C is reached. Then some more
Add toluene (400ml) and reflux for 3 hours under azeotropic conditions.
Flow. Cold welding, dissolve this suspension in chloroform and water.
Wash and dry with sodium bicarbonate. After distilling off the solvent,
The residue was mixed with ethyl acetate-diisopropyl ether mixture (1
: L v/v), 3,4-dihydro
-6-(3,4-dimethoxyphenyl)-2-methylpi
Rimidin-4-one (33.6 g) is obtained. mp, 228-235℃ IR (line 1-l)'1650cm'NMR (
CDC13-C[)30D, δ): 7.8-7.5
(2)1. m＞. 6.94 (LH, d, J=8Hz>, 6.69 (
IH, s), 4.01 (3H, s), 3.96 (
3H,s), 2.55 (3H,s) Production Example 2 3.4-dihydro-6-(3,4-dimethoxyphenyl
)-2-methylpyrimidin-4-one (2,0 g) of N
, N-dimethylformamide (20 ml) Nakano suspension,
Potassium tert-butoxide (108 animals) and methiodide
(1.0 ml) and stirred at room temperature for 1 hour. this
The mixture is poured into water and extracted with ethyl acetate. organic layer
Column chromatography using silica gel
, chloroform to give 3,4-dihydro-6-(
3,4-dimethoxyphenyl)-2,3-dimethylpyri
Midin-4-one (1,38 g) is obtained. mp, 187-190℃ IR (Nujol): 1670cm-'NMR
(CDC13,8)' 7.4-7.6 (2
)17m), 6.88 (LHld, J=9)1z
), 6.68 (LH,s), 3.95 (3H,
s＞. 3.93 <3)1. s), 3.55 <3H
,s), 2.61 <3H,'s) Production Example 3 3.4-dihydro-6-(3,4-dimethoxyphenyl
)-2-methylvinyl and non-4-one (2,4 g)
Nakano suspension of phosphorous oxychloride (20 ml) was refluxed for 2 hours and then evaporated.
Attach to the fastener. Add sodium bicarbonate aqueous solution and chlorine to the residue.
Add loform and stir at room temperature for 2 hours. remove organic layer
, wash with water. After distilling off the solvent, the residue was diluted with ethyl acetate-diiso
Dissolved in propyl ether mixture (1; 6, v/v)
do. The precipitate was filtered off, the solvent of the filtrate was distilled off, and the 4-chloro
rho-6-(3,4-dimethoxyphenyl)-2-methyl
Pyrimidine (2.09 g) is obtained. mp, 84-87°C IR (Nunyeol)' 1570. 1515c
m-1HMR(Cm)C10,8): 7.4-7.
8 (3H, m), 6.97 (LH. d, J-8) 1z), 3.97 <3H, s), 3
．． 94 (3H, s). 2.75 (38, s) Production Example 4 Heradroyl ethyl acetate (4.5 g) was diluted with 2-aminopylene
Lysine (0.84g) Giri phosphoric acid (13.7g) Nakano Nigori
Add dropwise to the solution at 60-70'C under stirring. reaction mixture
The mixture was stirred at 100°C for 3 hours and then poured into ice water (50ml).
pour. After extracting the aqueous solution with chloroform, washing with water and drying,
The dark oily residue obtained by distilling off the solvent was purified using silica gel.
chromatography using n-hexane-ethyl acetate.
Elute with The solvent of the fraction containing the target compound is distilled off,
The residue was triturated with ethanol-isopropyl ether,
2-(3,4-dimethoxyphenyl)-4-xo4
H-pyrido[1,2-a copyrimidine (3,8 g) was obtained.
Ru. mp, 165-167°C IR (Nujol): 1675. 1630c
m-1HMR (DMS○-1,8): 3.87 (
31 (, s), 3.90 (3H. s), 6.88-7.27 (3H, m>, 7.4
3-7.92 (4H, m) -9,01 (LH, q, J
=7Hz, 1.5Hz) Production Example 5 1) Ammonia of heladroyl ethyl acetate (100g)
Aqueous (28%, 10100O) Nakano suspension at room temperature for 6 days
Stir. Filter the precipitate and add ethanol and diisopropylene.
Washed with pyl ether and air dried to give 2-amino-3',
4/-dimethoxycinnamamide (40.98g
). mp, 204-207°C IR (Stripe 3-L)' 1640. 1610.
1580cm-1HMR (DMSO-da, 8)
'7.35 (2H1br s), 6.8-7.2 (
3H, m), 6.28 (2H, br s), 4.
80 (LH,s). 3.79 (6H,5) l) 2-amino-3/,41-dimethoxycinnamamide
(2.5 g) in ethanol (150 ml) Nakano suspension
, ethyl orthoformate (38ml) and concentrated hydrochloric acid (4ml)
1) and reflux for 2.5 hours. Add ethyl orthoformate (56ml) to this suspension again.
Well, reflux for 2 hours. The solvent of this solution was distilled off and the chloro
Dissolve in form. solution with sodium bicarbonate aqueous solution
Wash, dry with magnesium sulfate and remove the solvent under reduced pressure.
leave The resulting syrup was triturated with ethyl acetate to give 3.4
-dihydro-6-(3,4-dimethoxyphenyl)-4
-e” Rimidone (1.05 g) is obtained. mp, 248-249°C IR (Sujiwor): 1680. 1650c
m-1HMR (CDCl2-MeOHd4.8)
: 8.17 (LH,s). 7.4-7.7 (2H, m), 6.96 (IH
, d, J: 9Hz), 6.81 (IH, s),
3.96 (6H, s), 3.77 (IH, br
s) Production Example 6 The following compound was obtained in the same manner as in Production Example 3. 1) 4-chloro-6-(3,4-nemethoxyphenyl)
Pyrimidine. IR (Xjia-4): 1675. 1600c
m-1HMR (CDC1a, S)' 8.97 (L
Hls), 7.3-7.8 (3H1m), 6.9
6 (LH, d, J-8Hz), 3.96 (
3H,s). 3.94 (3H,s) 2>4-chloro-2-methyl-6-(4-pyridyl)pi
Limidine. mp: 99-102°C IR (Nujol): 1570. 1530c
m-'NMR (CDCl2.8>: 8.74 (2
H, d, J=7Hz), 7.88 (2H, d, J57
Hz), 7.57 (IH,s), 2.79
(3)1. s) 3〉4-chloro-5-(3,4-di
methoxyphenyl)-2-methylpyridine. mp: 72-75℃ IR (Sujoor) 2 1570cm-1HMR (
CDCl2. δ): 8.56 (LH,s), 7
．． 00 (3H,s>. 3.96 (3H,s), 3.93 (3H,s>,
2.76 (3H,5)4)4-chloro-6-(3,
4-dimethoxyphenyl)-2,5-dimethylpyrimidine
hmm. mp: 91-94℃ IR (Sujoor): 1560. 1510cm
-1HMR(CDC13,S)' 7. '
2-6.8 (3H1m>, 3.95 (6)1
゜s＞, 2.71 (3H,s), 2.40 (3
H,s) Production Example 7 The following compound was obtained in the same manner as in Production Example 1. 1) 3,4-dihydro-2-methyl-6-(4-pyridi
) pyrimidin-4-one. mp: >300°C IR (X di3-)' 1680. 1610c
m'NMR (C20-DCl, δ)' 9.06.
(2H, d, J = 7Hz>. 8.54 (28, d, J = 7Hz), 7.12 (I
H,s), 2.66(31,5) 2) 3,4-dihydro-5-(3,4-dimethokif)
phenyl)-2-methylpyrimidin-4-one. mp: 198-200°C IR (Scale)' 1660. 1600cm
-1HMR(CDCl2.l; )' 13.40.
(IH, br s), 8.07 (LH, s), 7
．． 4-7.0 (2H, m>, 6.87 (1
8,d. J=8)1z), 3.37 (6H,s), 2.4
8 (3H,5)3) 3,4-dihydro-6-(3
,4-dimethoxyphenyl)-2,5-dimethylpyrimi
Zin-4-one. mp: 205-215℃ IR<nujia-4) 7 1670cm-'NMR(
CDCl2. δ)' 13.7-12.9 (IH,
br s), 7.3-6,8 (3H, m), 3.
92 (6H,s), 2.53 (3)1. s
). 2.17 (3H,s) Production Example 8 The following compound was obtained in the same manner as in Production Example 2. 1) 3,4-dihydro-6-(3,4-dimethoxyphene)
Nyl)-2-ethyl-3-methylpyrimidin-4-one
. mp: 180-184°C IR (Nujol)' 1670. 1600c
m'NMR (CDC13,8)' 758 (IH1
ddJ=8Hz, J=2Hz>. 7.53 (LH, d, J-2Hz), 6.87 (
IH, d, J-8Hz>. 6.66 (IH, s>, 3.93 (6H,
s), 3.52 (3H, s). 2.80 (2H, q, J near Hz>, 1.40
(3H, t, J=7Hz)2) 3,4-di
Hydro-6-(3,4-dimethoxyphenyl)-3-eth
Tyl-2-methylpyrimidin-4-one. mp: 129-132℃ IR (Sujoor)' 1660. 1600c
m-1HMR (CDCl2.8): 7.4-7.7
(2H, m), 6.90 (1) 1°d, J=9H
z), 6.66 (IH,s), 4.10 (
2H, q-J=7Hz), 3.93 (3H, s)
, 3.90 <3H,s), 2.61(3H,
s), 1.34 (3H, t, J=7Hz>3)
3,4-dihydro-6-(3,4-dimethoxyphenyl
)-3-methylo rimidin-4-one. mp: 175-178℃ IR (Nujol)' 1680. 1600c
m-1HMR (CDCl2.8): 8.10
(IH, s), 7.4-7.6 (2H. m>, 6.89 (IH, d, J=9Hz>, 6.7
7 (IH, s). 3.93 (3H,s), 3.90 (3H,s),
3.54 (3H,s>4)3.4-dihydro-6-
(3,4-dimethoxyphenyl)-2,3,5-trimethane
Chilpyrimidin-4-one. mp: 115-118℃ IR '1650. 1600c
m-'NMR (CDCl2.8) = 7.3-6.8 (
3)1. m), 3.93 <6H. s), 3.57. (3H,s), 2.56 (
3H,s), 2.16 (3H. 5) 3,4-dihydro-6-(3,4-dimethoxy
phenyl)-3-ethylpyrimidin-4-one. mp' 150-153℃ IR (Nunthal>: 1670. 1600c
m-1HMR (CDC13,8)' 8.10 (L
H9s), 7.7-7.4 (2H9m), 6.96
<IH, d, J=9Hz), 6.76 (IH, s
). 3.98 (2H, q, J=7)1z), 3.96
(6H,s), 1.41 (3H,t, J=7Hz) Production Example 9 The following compound was obtained in the same manner as Production Example 5. 3,4-dihydro-6-(3,4-dimethoxyphenyl
)-2-ethylpyrimidin-4-one. mp: 195-200℃ IR (Sujoor): 1670. 1600c
m-1HMR(CDCl2.δ) = 13.3 (IH
, br s), 7.5-7.8 (2H, s), 6.
89 (1)1. d, J=9Hz), 6.67 (I
H,s). 3.95 (3H,s), 3.93 (3H,s)
, 2.83 (2H, q. J=8)1z), 1.44 (31,t, J=8H
z) Factor J191 3.4-dihydro-6-(3,4-dimethoxyphenyl
)-3-methyl-4-(2,4,6-trimethylphenylene
limino)-2-(xH)-rrimidone (5.0 g)
Phosphorous oxychloride was added. The mixture was refluxed for 7 hours and then vacuumed.
It was evaporated down to the bottom. Grind the resulting syrup in ice water,
Neutralized with aqueous sodium bicarbonate and extracted with chloroform
. The extract was dried and evaporated under reduced pressure. Clean the residue
Subjected to silica gel flomatography using loform
2-chloro-3,4-dihydro-6-(3゜4-dihydro-6-(3゜4-dihydro-6-
methoxyphenyl)-3-methyl-4-(2,4,6-
1-limethylphenylimino)pyrimidine (3,26g
) was obtained. Melting point: 159-162°C IR (Nujol)' 1640. 1590c
m-1HMR(CDCl2.δ)' 7.40 (I
H, d, J=2Hz), 7.27 (IH, dd, J:
2Hz, J=9Hz), 6.91 (2H,s),
6.86(11(,d,J=9)1z), 6.04
(11(,s), 3.92 (3Ls). 3.87 (3H,s), 3.83 (3H,
s)', 2.28 (3H,s>. 2.05 (6H,s>) Example 2 2-chloro-3,4-dihydro-6-(3,4-dimethod)
xyphenyl)-3-methyl-4-(2゜4.6-tri
Methylphenylimino)pyrimidine (1.5g)
10% palladium-carbon suspension in alcohol (20 ml)
(0.8 g) was added. The mixture was heated under a hydrogen atmosphere (1 atm.
) for 40 minutes. After removing the catalyst by filtration, the filtrate was placed under reduced pressure.
It was concentrated by evaporation. Neutralize the residue with aqueous sodium bicarbonate solution
, extracted with ethyl acetate. extract with magnesium sulfate
Dry and evaporate under reduced pressure. Chlorophorem the residue
For silica gel flomatography using
The fractions containing the target compound were combined and concentrated under reduced pressure.
The resulting residue was recrystallized from ethyl acetate to obtain 3,4-dihydro.
rho-6-(3,4-dimethoxyphenyl)-3-methyl
-4-(2,4,6-trimethylphenylimino)pyri
Midin (0.36g) was obtained. Melting point: 180-182°C IR (x diat, cm-'): 1640.
160ONMR (CDCl2.8): 7.81 (
IH, s), 7.29 (LH, d. J=2Hz), 7.08 (1)1. dd, J=2H
z, J=8Hz), 6.74(2)1. s), 6.
68 (LH, d, J=8Hz), 5.97 (LH
,s). 3.84 (3)1. s), 3.80 (3H, s)
, 3.53 (3H,s). 2.24 (3H,s), 2.00 (6H,s>
Fire' U1 Main 2-chloro-3,4-dihydro-6-(3,4-dimeth
xyphenyl)-3-methyl-4-(2゜4.6-tri
Methylphenylimino)pyrimidine (1.5g)
N-Methylhensylua was added to the suspension in Nord (15 ml).
Min (1.47 ml) was added. Reflux the mixture for 5 hours
did. The resulting suspension was dissolved in chloroborm and
Wash with water, dry with magnesium sulfate and evaporate under reduced pressure.
Shrunk. The resulting syrup was dissolved in diisopropyl ether.
Triturate and filter to give 3,4-dihydro-6-(3,4
-dimethoxyphenyl)-3-methyl-2-(N-methy
-N-benzylamino)-4-(2,4,6-trimethane)
Obtained tylphenylimino)pyrimidine (1.18g)
. Melting point: 96-98°C IR (sujoor, +-')' 1620.
160ONMR (CDCN 3,8)' 6.5-
7.5 (10H, m), 5.86 (1)1. s),
4.58 (2)! , s), 3.85 (3H, s>
, 3.82 (3H,s), 3.78 (3H,s)
, 2.93 (3H, s), 2.28 (3H, s)
, 2.08 (6H,s) Example 4 In the same manner as in Example 3, 2-chloro-3,4-dihydro
-6-(3,4-dimethoxyphenyl)-3-methyl-
4-(2,4,6-trimethylphenylimino)pyrimi
gin (3.0 g) and 50% dimethylamine aqueous solution (
3,4m1), 3,4-dihydro-6-(3,4-
dimethoxyphenyl)-2-dimethylamine-3-methy
Ru-4-(2,4,6-trimethylphenylimino)hydrogen
1.82g of 0.0s.midine was obtained. Melting point: 124-125°C IR (sujirol, cm-1): 164ONM
R(CDCl23.δ): 7.53 (LH, d,
J=2Hz>, 7.30 (IH, dd, J:2Hz,
J=5.5Hz>, 6.86 (2H, s). 6.82 (IH, d, J=5.5Hz), 5.8
1 (IH, s). 3.85 (3H, s), 3.83 (3H,
s), 3.62 (3H, s). 2.94 (6H,s), 2.24 (3Ls
), 2.01 (6Ls) Example 5 In the same manner as in Example 3, 2-chloro-3,4-dihydro
-6-(3,4-dimethoxyphenyl)=3-methyl-
4-(2,4,6-trimethylphenylimino)
Midine (3,0 g) and N-methylaniline (2,4
5 m1), 3,4-dihydro-6-(3,4-dihydro-6-(3,4-dihydro)
methoxyphenyl)-3-methyl-2-(N-methyla
nilino)-4-(2,4゜6-trimethylphenylimi
c) Pyrimidine (2.47 g) was obtained. Melting point: 164-165°C IR (sudial, cm-1)' 1635NM
R(CDCj!s,S)' 7.6-6.6
(10H, m), 5.90 (LH, s), 3.
86 (6H, s), 3.48 (3H, s), 3
．． 20 (3H,s), 2.26 (3H,s),
2.03 (68,s) trap and (ffil 6 2-chloro-3,4-dihydro-6-(3,4-dimethod)
xyphenyl)-3-methyl-4-(2゜4.6-tri
Methylphenylimino)hyrimidine (1,07g)
Ethanol (10ml) to Nakano suspension 2-? Racing (0
, 70g) was added. Reflux the mixture for 3 hours and cool to room temperature.
and concentrated by evaporation. Dissolve the residue in chloroform and add heavy carbon
Washed with an aqueous sodium chloride solution. Magnesium sulfate removes the organic layer.
The mixture was dried by evaporation and concentrated. The residue was dissolved in chloroform-meth
Silica gel chromatography using alcohol (95:5)
3,4-dihydro-6-(3,4-dimethyl)
toxyphenyl)-3-methyl-2-(1-e)
)-4-(2,4,'6-drimethylphenylimino)
) Hi-rimidine (0.69 g) was obtained. Melting point: 185-189°C IR (sudirol, cm-1): 1630. 1540
．． 152ONMR (CDCl2.δ): 7.0-
7.2 (2H, m), 6.5-6.8 (3H, m>
, 5.76 (IH,s), 3.79 (6H,
s), 3.66 (3H, s), 3.3 (4H,
br, s), 3.0 (4H, br, s). 2.23 <38. s), 2.02 (6H, s)
Example 7 2-chloro-3,4-dihydro-6-(3,4-dimeth
xyphenyl)-3-methyl-4-(2゜4.6-tri
Methylphenylimino)hyrimidine (10,0g)
Hydrazine in chloroform (100ml) Nakano suspension
(3,66 ml) was added. The mixture was refluxed for 6 hours,
Evaporate and concentrate under reduced pressure. Filter the residue using chloroform.
3,4-dihydro
-6-(3,4-dimethoxyphenyl)-2-hydracy
Tanoh 3-methyl-4-(2,4,6-1-limethylphthalate)
henylimino)pyrimidine (3.46 g) was obtained. Melting point: >300°C IR (nucle, cm-1)' 1645. 1
635. 159ONMR (CDCl2-CD30D,
l; ): 6.8-7.2 (5H, m>, 5
．． 22 (IH, s>, 3.87 (6M, s),
3.57 (3H,s), 3.2-4.2
(3H, br, m>, 2.27 (3) 1.s
), 2.05(6)1. s) Example 8 2-chloro-3,4-dihydro-6-(3,4-dimeth)
xyphenyl)-3-methyl-4-(2゜4.6-tri
Methylphenylimino)-rimicin (3.0g)
Roform (15ml) Nakano; Formylhydrazine in the solution
(1.36g) was added. The mixture was refluxed for 6 hours and brought to room temperature.
Cooled. The formed precipitate was filtered off, and the filtrate was concentrated by evaporation under reduced pressure.
Shrunk. The residue was chromatographed on silica gel using chloroform.
3,4-dihydro-6-(3,4
-dimethoxyphenyl)-2-(2-formylhydrazi
-3-methyl-4-(2,4,6-trimethylphenylene)
Nylimino)pyrimidine (0.84 g) was obtained. Melting point: 136-143°C IR (sujirol, cm-'): 1680.
1590NMR (CDCl2.8')' 7
．． 94 (IH,s), 6.8-7.5 (5
H. m>, 5.10 (IH,s), 3.85 (
6H,s), 3.8(3H,s), 2.27
(3H,s), 2.17 (6H,s>Example 9 2-chloro-3,4-dihydro-6-(3,4-dimethod)
xyphenyl)-3-methyl-4-(2゜4.6-doli
Drying of methylphenylimino)hyrimidine (5.0g)
Add methyl mercapta to Nakano suspension of ethanol (50ml)
Sodium (1.06g) was reduced. Bring the mixture to room temperature
Stir for 3 hours, pour into water (100ml), and chlorinate.
Extracted with loform. After concentrating the extract by sulfur evaporation, the residue
was triturated with ethyl acetate to give 3,4-dihydro-6-(3
,4-dimethoxyphenyl)-3-methyl-2-methyl
Thio-4=(2,4,6-drimethylphenylimino)
Pyrimidine (3.51 g) was obtained. Melting point: 172-173℃ IR (sujiwor, cm'): 164ONMR
(CDCl2.8>' 7.50 (1) 1.d, J
= 2Hz), 7.32 (IH, dd, J-2Hz, J
=9Hz>, 6.88 (2H,s>, 6.8
2 (LH, d, J=9Hz), 5.92 (IH
,s>, 3.86 (6H,s). 3.69 (3H,s), 2.68 (3H,s)
, 2.28 (3H,s). 2.02 (6H,s) Example 10 3.4-dihydro-6-(3,4-dimethoxyphenyl
)-3-Methyl-2-(1-hyazazinyl)-4-(
2,4,6-drimethylphenylimino)Il:6limino
gin (0.31 g) in tetrahydrofuran (10 ml)
Triethylamine (0.11ml) and Nakano suspension
Add 4-fluorobenzoyl chloride (0.69ml)
Ta. The mixture was stirred at room temperature for 1 hour and then added with methanol (5 ml
) was added to stop the reaction. After distilling off the medium i, dissolve the residue in vinegar.
Dissolved in ethyl acid. Wash the solution with water and add magnesium sulfate
and evaporated under reduced pressure. Chloroform the residue
-Silikage J Rechroma using methanol (95:5)
3,4-dihydro-6-(3,4
-dimethoxyphenyl)-2-[4-(4-fluorobe
bizerazin-1-yl]-3-methyl-4-
(2,4,6-drimethylphenylimino)
(0.34 g) was obtained. Melting point: 117-121°C IR (Sjoor, cm-')' 1630.
1540. 152ONMR (CDCl2.8)'
6.6-7.6 (9H, m), 5.88 (IH. s), 3.84 (6H, s), 3.75 (4,
H, br, s), 3.67 (3H, s), 3.2-
3.5 (4)1. m), 2.27 (3H, s). 2.03 (6H,s) Example 11 3.4-dihydro-6-(3,4-dimethoxyphenyl
)-2-(2-formylhydrazino)-3-methyl-4
-(2,4,6-drimethylphenylimino)pyrimidine
(0,81 g) and priphosphoric acid (82 g, phosphoric acid and
The mixture (116%) was stirred at 110 °C for 2 h.
, cooled to room temperature. Pour the reaction mixture into water and hydroxylate
Neutralized with aqueous sodium solution. Filter the precipitate and wash with water
, 7,8-dihydro-5-(3,4-dimethoxyphenyl
)-8-methyl-7-(2,4,6-drimethylphenylene)
(nylimino)-1,2,4-triazolo[4,3-a
Pyrorimidine (0.65 g) was obtained. Melting point: 125-130°C IR (nu9-1, am-1>' 1655.1
57ONMR (DMSO-d6.δ): 8.58
(IH, s>, 6.8-7.3 (5H, m), 5.
40 <LH, s), 3.80 (6H, s), 3
．． 73 (3H, s), 2.21 (3H, s), 1
．． 99 (68,s) Example 12 2-chloro-3,4-dihydro-6-(3,4-dimethod)
xyphenyl)-3-methyl-4-(2゜4.6-hri
Medelphenylimino)hyolimidine (1.0g)
Suspended in a mixture of tanol (9 ml) and water (1.5 ml)
Sodium azide (0,163 g) was added to the liquid. mixture
The mixture was stirred at 50-55°C for 1 hour. solvent removed
After that, the residue was washed with water and collected by filtration to give 4,5-dihydro-7-
(3,4-dimethoxyphenyl)-4-methyl-5-(
2,4,6,-trimethylphenylimino)tetracylo
[1,5-a]pyrimidine (0.80 g) was obtained. Melting point: 198-200℃ IR (sudicol, cm-1>' 166ONM
R(CDCl2.δ): 6.8-7.5 (5H,
m), 5.90 (LH. s), 3.93 (9H, s), 2.33 (3)
1. s), 2.07(6H,S) Example 13 3.4-dihydro-6-(3,4-dimethoxyphenyl
)-3-methyl-2-(N-methyl-N-benzylamide
-4-(2,4,6-trimethylphenylimino)
- Limidine (1,0 g) in tetrahydrofuran (20 m
l) Methyl iodide (2.58ml) was added to the solution in
. The solution was refluxed for 10 hours and cooled to room temperature. reaction mixture
was concentrated by evaporation under reduced pressure, and the residue was purified using chloroform.
2-benzylimine was subjected to silica gel chromatography.
No-6-(3,4-dimethoxyphenyl)-1,3-di
Methyl-1,2,3,4,-tetrahydro-4-(2,
4゜6-trimethylphenylimino)pyrimidine (0,
62g) was obtained. Melting point: 97-100°C 'LR (Sudicol, Cm-1)' 1570.
155ONMR (CDC13,8): 6.7-7,
7 (IOH, m>, 5.57 (LH, s), 5
．． 03 (2H,s), 3.85 (3H,s
), 3.84 (38,s), 3.30 (3H,
s), 3.25 (3H, s), 2.33 (3H,
s), 2.12 (68,s) Example 14 In the same manner as in Example 13, 3.4-dihydro-6-(3
,4-dimethoxyphenyl)-2-dimethylamino-3
-Methyl-4-(2,4,6-trimethylphenylimi
) Pyrimidine (0.8 g) and methyl iodide (2,
45ml), 6-(3,4-dimethoxyphenyl
)-1,3-dimethyl-2-methylimino-4-(2,
4,6-drimethylphenyl)-1,2,3,4-tet
Lahydropyrimidine (0.47 g) was obtained. Melting point': 150-151°C IR (streak, cm-1)' 1570.
155ONMR (CDC13=8>'7
．． 63 (IH, d, J=2Hz), 7.26 (
IH, d, J=2Hz, J=9Hz), 6.97
(2H, s), 6.79 (LH, d, J=9Hz)
, 5.54 (LH,s), 3.91 (3H,s
). 3.86 (3H,s>, 3.33 (3H,s)
, 3.27 (6H,s). 2.32 (3H,s), 2.10 (6H,s>
Example 15 In the same manner as in Example 13, 3,4-dihydro-6-(3
,4-dimethoxyphenyl)-2-(N-methylanili
-3-methyl-4-(2,4゜6-trimethylphenylene)
nylimino)pyrimidine (0,4 g) and methioiodide
6-(3,4-dimethoxy)
phenyl)-1,3-dimethyl-2-phenylimino-
4-(2,4,6-trimethylphenylimino)-1,
2,3,4-tetrahydropyrimidine (0,4mg)
I got it. Melting point: 145-14'7°C IR (stripe 1-l, am-1): 1580.
1540. 152ONMR (CDCl2.δ):
7.6-6.6 (10H, m), 5.65 (LH,
s), 3.83 (38, s>, 3.80 (
3H,s), 3.68<3H,s), 3.26
(3)1. s), 2.33 (38,s),
2.10<68. s) Example 16 4-chloro-6-(3,4-dimethocyphenyl)-2-
Methylpyrimidine (2.0g) and 2°4.6. -
A mixture of trimethylaniline (5.3ml) was heated to 120°C.
The mixture was stirred for 1 hour. After cooling, the mixture was triturated with ethyl acetate.
did. The precipitate was collected and dissolved in chloroform. solution
Wash with aqueous sodium bicarbonate solution and dry with magnesium sulfate.
Dry and evaporate to give 6-(3,4-dimethoxyphenylphenyl)
)-2-methyl-4-(2,4,6-trimethylphenylene)
nylamino)pyrimidine (2.39 g) was obtained. Melting point: 716g-170°C IR (sudicol): 1600. 1580.
1520cm-1HMR (CDCl2.δ): 7
．． 55 <IH, d, J=2Hz), 7.28 (IH
, dd, J=2Hz, J=8Hz>, 6.96 (2
H, s), 6.80 (IH, d, J=, 8Hz),
6.7-7.4 (IH, brs), 6.02<
IH,s), 3.92 (3H,s), 3.8
6 (3H,s), 2.51(31(,s>,
2.32 (3H,s), 2.19 (6)1. s
) Example 17 In the same manner as in Example 16, the following compound was obtained. 1) 6-(3,4-dimethoxyphenyl)-4-(1-
Indolinyl)-2-methylpyrimidine Melting point: 123-125°C IR (striped seal): 1580cm-1HMR
(CDC13, δ): 8.42 (IH, d, J=
8Hz), 6.8-7.7 (6Lm), 6.7
0 (ILs), 3.97 (3) 1°s),
3.90 (3H, s), 3.8-4.2 (2)
1. m>, 3.0-3.4 (2)1. m>,
2.69 (38,5)2)2-amino-3,4-dihy
Dro-6-(3,4-dimethoxyphenyl)-3-methy
Ru-4=(2,4,6-trimethylphenylimino)hy
0 Limidine melting point: 192-195℃ IR (Stripe Seal > 7 1630.1600cm-
13) 3,4-dihydro-6-(3,4-dimethoxyf
phenyl)-3-methyl-2-(1,2,3゜6-tetra
hydro-lysin-1-yl)-4-(2,4,6-tri
Methylphenylimino)pyrimidine Melting point: 161-163°C IR < streak seal): 1640cm-14)3
．． 4-dihydro-6-(3,4-dimethoxyphenyl)
-2,3-dimethyl-4-(2,4゜6-trimethylphenyl
(Phenylimino)pyrimidine Melting point: 163-168℃ IR (Stripe 3-l): 1630cm-1s)
2-(3,4-dimethoxyphenyl)-4-(2,4,
6-trimethylphenylimino)-4H-pyrido[1,
2-a] Pyrimidine Melting point: 187-191°C IR (Stripe Seal) '1640. 1605c
m'6) 6-(3,4-dimethoxyphenyl)-2-meth
thyl-4-[N-methyl-N-(2,4,6-dorimethy)
(ruphenyl) aminocopyrimidine melting point"124-125
°C IR (Stripe Seal L 1580cm-'7) 6-(3
,4-dimethoxyphenyl)-4-(2,4,6-doli
Methylphenylamino)pyrimidine Melting point: 164-166°C IR (Stripe Seal)' 1620. 1600
．． 1590cm-'NMR (CDC13,8')
8.63 <LH,s>, 7.61 (LH
. d, J-2Hz), 7.30 (1)1. bd,
J=2H, 8Hz). 6.97 (2H, s), 6.85 (IH, brs), 6
．． 83 (IH, d, J=8Hz>, 6.27 (
LH,s), 3.94 (3H.s), 3.89 (3)1. s>, 2.33
(3H,s), 2.21(6H,s>8)6-(3,4-dimethoxyphenyl)-4-[N-
Methyl-N-(2,4,6-drimethylphenyl)ami
Nocopyrimidine Melting point: 124-126°C IR (striped seal): 15g5. 1520c
m-19) 3,4-hydro-6-(3,4-dimethoxy)
Cyphenyl)-3-methyl-4-(2,4,6-trimethane)
Tylphenylimino) rimicin hydrochloride Melting point: 16
5-173℃ IR (Stripe Seal)' 1630. 1580c
m'10) 3,4-dihydro-6-(3,4-dime
toxyphenyl)-3-methyl-4-(2,4,6-t
Limethylphenylimino)pyrimidine Melting point: 180-
182℃ XR (streak seal): 1640. 1600c
m-111) 1-acetyl-6-(3,4-dimethoxy
phenyl)-3-methyl-1,2,3,4-tetrahydride
rho-4-(2,4,6-trimethylphenylimino)pi
Limidine melting point j 173-175°C IR (suji 9-l): 16g5. 1630c
m-112) 3,4-dihydro-6-(3,4-dimethyl
toxyphenyl)-3-ethyl-2-methyl-4-(2
,4,6-trimethylphenylimino)pyrimidine Melting point: 118-120°C tR<sudicol)' 1630cm-113)
4-[1-(1,2,3,6-tetrahydro)pyridyl
]-6-(3,4-dimethoxyphenyl)-2-methyl
Pyrimidine melting point: 112-114°C IR (meso-3-ol): 1610. 1585c
m-1HMR (CDCl2.δ): 7.3-7.6
(2H, m), 6.85 (IH, d, J=8Hz)
, 6.55 (IH,s), 5.7-6.0 (2H
, m), 3.7-4.2 <4Lm), 3.95
(3H, s>. 3.89 (38, s), 2.57 <3H,
s), 2.0-2.5(2)1. m> 14) 6-(3,4-dimethoxyphenyl)-2-methy
4-(1-piperazinyl)pyrimidine Melting point: 13g-140°C -IR(N9-9-)' 1600. 1580c
m-'NMR(CDCl2.l;)' 7.56
(LH, d, J=2Hz), 7.46(1)1. d
d,, T=2Hz, 8Hz), 6.87 (11
(,d. J:8Hz>,6.59 (1)t,s), 3.9
6 (3H, s). 3.90 (38,s), 3.75-3.50 (28
, m), 3.05-2.80 (2H, m), 2.
56 (3H,5)15)4-[4-(2,4-dichloro
lo-5-sulfamoylbenzoyl)-piperaziny 1
-yl]-6-(3,4-dimethoxyphenyl)-2-
Methylpyrimidine melting point: 150-460°C IR (Sudicol) 7 1640,4580cm-
116) 6-(3,,4-dimethoxyphenyl)-3-
Methyl-1,2,3,4,-tetrahydro-4-(2,
4,6-trimethylphenylimino)pyrimidine Melting point: 165-166°C IR (sudicol): 1620. 1605.
1590cm-117)2-methyl-6-(4-pyri
zyl)-4-(2,4,6-drimethylphenylamino
) Pyrimidine Melting point: 154-156℃ IR (Sudicol): 1590cm-1HMR
(CDCl2.8) ' 8.60 (2H, br s
), 7.65 (2H, br, d, J=5Hz>, 6
．． 95 (2H, s), 6.31 (LH, s), 2
．． 52 (3H, s), 2.33 (3H, s). 2.20 (6)1,5) 18) 3.4-dihydro-6-(3,4-dimethocyfe
Nyl)-2-ethyl-3-methyl-4-(2,4,6-
Trimethylphenylimino)pyrimidine Melting point: 19B-199°C IR (1630cm'19)
4,5-dihydro-7-(3,4-dimethoxyphenylphenyl)
)-4-methyl-5-(2,4,6-trimethylphenylene)
nylimino)tetracylo[1,5-a]pyrimidine hydrochloride
Melting point = 221°C (decomposition) IR (sudicol)' 1635. 1595.
2380cm-120) 5-(3,4-dimethoxyf)
phenyl)-2-methyl-4-(2,4,6-drimethyl
Phenylamino) pyrimidine Melting point: 202-204°C IR (stinyl)' 1590. 1550c
m-1HMR (CDCl2.δ): 8.10 (I
H, s), 7.10-6.85 (5H, m>, 6.
20 (LH, br s), 3.92 (6H, s)
. 2.44 (3H,s), 2.29 (3H,s),
2.14(6H,s) 21) 6-(3,4-dimethoxyphenyl)-2゜5-
Dimethyl-4-(2,4,6-dimethylphenylamine)
B) Pyrimidine Melting point: 168-170°C IR (Nujol): 1580. 1520c
m'''INMR(CDCl2.S)' 7.30-6
．． 80 (5H1m>, 5.89 (LH, br s),
3.93 (6H, s), 2.45 (3H, s)
. 2.33 (3H, s), 2.26 (9H, s>2
2) 6-(3,4-dimethoxyphenyl)-4-(4-
Benzhydryl biracin-1-yl)-2-methylpyl
Limidine melting point: 179-181°C IR (Nujol): 1580. 1520c
m-'NMR (CDCl2.8): 7.6-7.0
(12H, m>, 6.83 (LH, d, J=9Hz
>, 6.54 (IH,s), 4.24 <LH. s), 3.94 <38. s), 3.88 <38
．． s), 3.8-3.5 (4H, m>, 2.56
(3H,s), 2.6-2.3(4H,m> Example 18 3.4-dihydro-6-(3,4-dimethoxyphenyl
)-2,3-dimethylpyrimidin-4-one (0,33
g) Nakano suspension of phosphorus oxychloride (10 ml) was refluxed for 1 hour.
Drain and evaporate. Add 2.4゜6-drimethyla to the residue.
Add Nilin (3.6ml) and stir at 100°C for 2 hours.
did. After cooling, the mixture was dissolved in chloroform and diluted with bicarbonate.
Washed with aqueous sodium solution. The organic layer was dried with sodium sulfate and chromatographed on silica gel.
The 3,4-dihydrogen
Dro-6-(3,4-dimethoxyphenyl) -2,3
-dimethyl-4-(2,4,6-trimethylphenyl
Mino)pyrimidine (0.21 g) was obtained. Melting point: 163-168°C IR: 1630cm-'NMR
(CDCl2.8): 7.42 (I
H, d, J=2Hz), 7.20<LH, dd,
J=2Hz, J=7Hz>, 6.85 (2H,s)
, 6.77 (LH, d, J=7Hz), 5.98
(IH,s), 3. '89 (3H, s). 3.85 (3H1s), 3.66 (3H,s), 2
．． 57 <3H,s). 2.26 (3H,s), 2.03 (6H,s)
Example 19 The following compound was obtained in the same manner as in Example 18. 1) 2-(3,4-dimethoxyphenyl)-4=(2,
4,6-trimethylphenylimino)=4H-pyrido[
1,2-a]pyrimidine Melting point: 187-191°C IR (Sujoor): 1640. 1605cm
-1HMR (CDC1a, 6i) '9', 45
(LH9d, J=7Hz>, 67-7.6 (8H,
m), 6.07 <LH, s), 3.93 (3H
. s), 3.87 (3H, s), 2.28 (3H
,s>, 2.07(6H,5) 2) 2-Amino-3,4-dihydro-6-(3,4-dihydro-6-(3,4-di
methoxyphenyl)-3-methyl-4-(2,4,6-
Trimethylphenylimino)hyrimidine Melting point: 192-195°C IR (Nujol)' 1630. 1600c
m-'3)3,4-dihydro-6-(3,4-dimeth
xyphenyl)-3-methyl-2-(1,2,3゜6-
titrahydrolysin-1-yl)-4-(2,4,
6-Dorimethylphenylimino)hyrimidine Melting point: 161-163°C IR (nujol): 1640cm'4)6-
(3,4-dimethoxyphenyl)-2-methyl-4-[
N-methyl-N-(2,4,6-drimethylphenyl)
Aminocopyrimidine melting point: 124-125°C IR<1 syl)'1580cm-'NMR
(CDCl2.δ): 7.5L (LH
, d, J=2Hz), 7.15(18, dd, J=
2Hz, 8Hz), 6.95 (2)1. s), 6
．． 78(1)1. d, ] = 8Hz), 5.93 (L
H, s), 3.91 (3H. s), 3.84 (3H, s>, 3.36 (3H.
,s>, 2.65<38. s), 2.32 (3H
,s), 2.07 (6H,5)5)6-(3,4-
dimethoxyphenyl)-2-meth-4-(2,4,6
-drimethylphenylamino)pyrimidine Melting point: 168-170°C IR<X9): 1600. 1580, 1
520cm-16) 6-(3,4-dimethoxyphenyl
)-4-(1-indolinyl)-2-methylpyrimidine Melting point: 123-125°C IR (sujimil): 1580cm-'7)6
-(3,4-dimethoxyphenyl)-4-(2,4,6
-Dolimethylphenylamino)pyrimidine Melting point: 164-166°C IR (sujimil): 1620. 1600.
1590cm-'8) 6-(3,4-dimethoxyphenylene)
)-4-[N-methyl-N-(2,4,6-drimethyl)
(ruphenyl) aminocopyrimidine Melting point: 124-126℃ IR (sujimil): 1585.1520
am-19) 3,4-dihydro-6-(3,4-dimetho
xyphenyl)-3-methyl-4-(2,4,6-doli
Methylphenylimino)pyrimidine salt melting point: 165-173°C IR (sujimil): 1630.1580
cm-110) 3,4-dihydro-6-(3,4-dimethyl
Toxyphenyl)-3-methyl-4-(2,4,6-do
Limethylphenylimino)pyrimidine Melting point: 180-
182℃ IR (suji meal): 1640.1600
cm-111) 1-acetyl-6-(3,4-dimethoxy)
Cyphenyl)-3-methyl-1,2,3,4-tetrahy
Dro-4-(2,4,6-drimethylphenylimino)
Pyrimidine melting point: 173-175°C IR (Sujimil) 2 1685. 1630
am-112) 3,4-dihydro-6-(3,4-dimethyl
toxyphenyl)-3-ethyl-2-methyl-4-(2
,4,6-toIJ methylphenylimino)pyrimidine Melting point: 118-120'C IR (Sujimil)' 1630 am-1H
MR (CDCl2.δ): 7.5-6.6 (5H
, m), 5.96 (IH, s), 4.32 (
2H,q, J=7Hz), 3.86 (3H,s)
. 3.83 (3H,s), 2.60 (3H,s)
, 2.25 (3H,s). 2.04 <68. s), 1.46 (3H,t,
J=7Hz>13) 4-[1-(1,2,3,6-tet
pyridylco-6-(3,4-dimethoxyphene)
,;L)-2-methylpyrimidine Melting point: 112-114°C IR (sujimil): 1610,1585
cm""14) 6-(3,4-dimethoxyphenyl)-
2-Methyl-4-(1-t4radinyl)pyrimidine Melting point: 138-140°C IR (sujimil): 1600,1580
cm-115) 4-[4-(2,4-dichloro-5-su
rufamoylbenzoyl)hyserazin-1-yl]-6
-(3,4-dimethoxyphenyl)-2-methylpyrimi
Melting point: tso-tao℃ IR (suji 3-l): 1640, 1580
cm-116)6-(3,4-dimethoxyphenyl)-
3-Methyl-1,2,3,4-tetrahydro-4-(2
,4,6-)limethylphenynoreimino)hyrimidine Melting point: 165-166°C LR (Nuji→-L)' 1620.1605.1
590 cm-'17)2-methyl-6-(4-pyri
zyl)-4-(2,4,6-trimetherphenylamino
) Pyrimidine Melting point: 154-156°C IR(X*a-R)' 1590 am-11
8) 3,4-dihydro-6-(3,4-dimethoxyfe
Nyl)-2-ethyl-3-methyl-4-(2,4,6-
Dolimethylphenylimino)pyrimidine Melting point: 19g-199℃ IR (Sudishyl) '1630 am'NM
R(CDCl2,8)' 7.50 (IH,d,
J=2Hz) + 7.25(1)1. dd, J=9)
1z, J=2Hz), 6.84 (2H,s
), 6.79 (IHld, J=9Hz>,
6.00 (IH,s), 3.89
(3B, s). 3.86 (31,s), 3.65 <3
)1. s), 2.82 (2H, q. J=8Hz>, 2.27 (3H, s)
, 2.03 (6H,s) , 1.42(
3H, t, J=8Hz) 19) 4,5-dihydro-7-(3,4-dimethoxy!phenyl)-4-methyl-gu(2,4,6-drimethyl)
ruphenylimino) tetracylo[1,5-a copyrimidium
Melting point: 221°C (decomposition) IR (striped seal): 1635.1595.2
380 cm-120) 5-(3,4-dimethoxyf)
phenyl)-2-methyl-4-(2,4,6-trimethyl
Phenylamino)H0rimidine Melting point: 202-204℃ IR (Stripe Seal)' 1590.1550
am-121)6-(3,4-dimethoxyphenyl)-
2-Methyl-4-(2,4,6-drimethylphenoxy
) Pyrimidine Melting point: 122-125°C IR (streak seal): 1580 ctn-'
22) 3,4-dihydro-6-(3,4-dimethoxyf
phenyl)-3-ethyl-4-(2,4,6-drimethyl
Phenylimino)pyrimidine Melting point: 111-113℃ IR (Stripe Seal) '1640 cm-'N
MR (CDCl2.δ): 7.96 (IH, s)
, 7.77 (LH, d. J-2Hz) , 7.22 (IH, dd, J=8H
z, J=2Hz), 6.89(2H,s>, 6
．． 80 (LH, d, J=8Hz>, 6.09 (
LH,s). 4, 13 (2H, q, J=7Hz), 3.93
(3H,s), 3.90 (3H,s), 2.30
(3H,s>, 2.08 (6H,s), 1.
50 (3H, t, J=7Hz> Example 20 6-(3,4-dimethoxyphenyl)-2-methyl-4
-(2,4,6-trimetherphenylamino)pyrimidine
(1.0 g) of N,N-dimethylformamide (15
ml) Potassium t-butoxide (0.37g) in medium temperature solution
and methyl iodide (0.34ml) were added and the mixture
was stirred at room temperature for 1.5 hours. The mixture was then soaked in ice water (2
00ml) and stirred for 1 hour. Collect the precipitate,
Washed with water, air-dried, recrystallized with ethanol, 6-(3,4
-dimethoxyphenyl)-2-methyl-4-[N-methy
Ru-N-(2,4゜6-drimethylphenyl)aminoco
Pyrimidine (0.58 g) was obtained. Melting point: 124-125℃ IR (sujifur)' 1580 cm-1H
MR (CDC13, δ): 7.51 (1) (, d
, J=2) (z>, 7.15<IH, dd, J=2
Hz, 8)1z), 6.95 (2H,s),
6.78 (IH, d, J=8Hz>, 5.93 (
1)1. s)-, 3,91(3)1. s). 3, 84 (3)1. s), 3.36 (3H,s
), 2.65 (3H,s). 2.32 (3)1. s), 2.07 (6H
,s) Example 21 The following compound was produced in the same manner as in Example 20. 1) 6-(3,4-dimethoxyphenyl)-4-[N-
Methyl-N-(2,4,6-1rimetherphenyl)ami
]Birimidine Melting point: 124-126℃ IR (Sujoor)' 1585.1520
am-1HMR (CDCIs, δ): 8.74 (
IH, s), 7.55 (IH, d. J=2Hz), 7.16 (IH, dd, J=2H
z, 8Hz>, 6.97<28. s), 6.7
9 (LH, d, J=8Hz>, 6.12 (
IH,s). 3.91 <38. s), 3.86 (3H, s)
, 3.37 (3H,s). 2.34 (3H,s), 2.08 (6)1,5
)2) 6-(3,4-dimethoxyphenyl)-2,5-
Dimethyl-4-[N-methyl-N-(2゜4.6-1-
rimetherphenyl)amine] H0rimidine Melting point: 148-149°C IR (Nujol): 1550.1525
cm'NMR (CDCIs, 8)' 7.1-6
．． 8 (5H1m>, 3.87 (6H, s), 3
．． 34 <38. s), 2.61 (3H, s)
, 2.29 (3H,s) , 2.10 (6H,s
), 1.30 (3H,s) Example 22 2-chloro-3,4-dihydro-6-(3,4-dimeth
xyphenyl)-3-methyl-4-(2゜4.6-doli
Tet of methylphenylimino)pyrimidine (5.0g)
Add ammonia gas to a medium-temperature solution of lahydrofuran (50 ml).
Blowing allowed saturation at 0°C. The solution was sealed and heated at 120° C. for 13 hours. obtained
The suspension was subjected to silica gel chromatography using chloroform.
Mu-methanol (95:5 v/v -90:10v
/v) to give 2-amino-3,4-dihydro-6
-(3,4-dimethoxyphenyl)-3-methyl-4-
(2,4',6-drimethylphenylimino)pyrimidine
(2.64 g) was obtained. Melting point: 192-195℃ IR (nudicol): 1630,1600
cm-1 HMR (CDCIs, δ) Near, 5-6.7
(5H, m), 5.74 (IH, s), 4.
6 (2)1. br s), 3.88 <6H,s
). 3.80 (38,s), 2.28 (3H,s)
, 2.07 (6H,s) Example 23 2-chloro-3,4-dihydro-6'-(3,4-dihydro
Toxyphenyl)-3-methyl-4-(2゜4.6-do
Limethylphenylimino)hyrimidine (2.08g)
Add 1°2.3.6-chi to the suspension in ethanol (20ml).
Add trahydropyridine (1.38 ml),
Refluxed for an hour. Collect the resulting precipitate and dissolve in chloroform
and washed with aqueous sodium bicarbonate solution and magnesium sulfate.
It was dried. After evaporation and concentration, the residue is diisopropyl ether.
3,4-dihydro-6-(3,4-dimethyl)
toxyphenyl)-3-methyl-2-(1,2,3,6
-tetrahydropyridin-1-yl)-4-(2°4.
6-drimethylphenylimino)pyrimidine (1,41
15g) was obtained. Melting point: 161-163°C IR: 1640 cm-1H
MR (CDCIs, δ): 7.45 (LH, d,
J=2Hz), 7.26<IH,dd, J=2.7
Hz＞, 6.83 (2H,s), 6.76(
LH, d, J = 7Hz), 5.82 (3H, s),
3.84 (6H, s). 3.82 (28,s), 3.63 (3H,
s), 3.3-3.6 (2H, m), 2.2-
2.6 (2H, br s), 2.26 (3H,
s). 2.02 (6H,s) Example 24 3.4-dihydro-6-(3,4-dimethoxyphenyl
)-3-methyl-4-(2,4,6-drimethylphenylene)
(lumino)pyrimidine (2,0 g) in ethanol (10
ml) and water (10 ml).
Sodium (1.04 g) was added and the mixture was refluxed for 1 hour.
Stirred for 5 hours. After removing the organic solvent, pour the mixture into water.
Suspended and extracted with ethyl acetate. The organic layer is treated with magnesium sulfate.
dried over 100 ml, concentrated by evaporation, triturated with ethanol,
-(3,4--dimethoxyphenyl)-3-methyl-1
,2゜3.4-tetrahydro-4-(2,4,6-tri
Obtained notylphenylimino)pyrimidine (1.18g)
Ta. Melting point: 165-166℃ IR (Nujol)' 1620.1605.1
590 cm-'NMR(DMSO-d6.δ)'
7.2-6.7 (6H,m>, 4.63(LH
,s), 4.38 (2H,s), 3.74
(6H,s), 2.92(3H,s), 2.1
8 (3H, s), 1.95 (6H, s) Example
25. The following compound was produced in the same manner as in Example 24. 1) 1-acetyl-6-(3,4-dimethoxyphenyl
)-3-methyl-1,2,3,4-tetrahydro-4-
(2,4,6-drimethylphenylimino)pyrimidine Melting point: 173-175°C IR (striped seal): 1685.1630 a
m-12) Tetrahydride instead of sodium borohydride
Using lithium aluminum hydride in lofuran, 6-
(3,4-dimethoxyphenyl)-2,3-dimethyl-
1,2,3,4-tetrahydro-4-(2,4,6-do
Limethylphenylimino)hyrimidine was obtained. Melting point: 141-146℃ IR (sudicol): 1620, 1590
cm-1HMR (DMSO-d6.δ): 7.
1-6.7 (5H, m>, 4.72 (LH, q,
J=6Hz>, 4.47 (LH,s), 3.
76 (6B, s>. 2.93 (3H, s), 2.18 (3H,
s), 1.97 (6H, s). 1.38 (3H, d, J=6Hz) Example 26 6-(3,4-dimethoxyphenyl)-3-methyl-1
,2,3,4-tetrahydro-4-(2゜4.6-doli
Methylphenylimino)pyrimidine (0,5g)
Acetic anhydride (1.0 ml) was added to the solution in gin (5 ml).
, the mixture was stirred at room temperature for 2.5 hours and water (150 ml)
and extracted with chloroform. Brine the organic layer
, dried over sodium sulfate and evaporated. residue
was subjected to silica gel chromatography and dissolved in chloroform.
and 1-acetyl-6-(3,4-dimethoxyphene).
Nyl)-3-methyl-1,2,3,4-tetrahydro-
4-(2,4,6-drimethylphenylimino)pyrimi
Gin (0.22 g) was obtained. Melting point: 173-175℃ IR (Stripe Seal) 7 1685.1630c
m-'NMR (CDCl2.su: 7.0-6.7 (
5H,m>, 5.47(LH,s), 5.07
(2H,s), 3.87 (3H,s>, 3
．． 81 (3H, s), 3.18 (3H, s),
2.26 (3H, s), 2.04 (6H, s)
, 1.77 (3H,s) Example 27 6-(3,4-dimethoxyphenyl)-2-methyl-4
-(1-Piperazinyl)pyrimidine (0,8g)
Triethylamine (0
, 39m1) and 2,4-dichloro-5-sulfa
Add moylbenzoyl chloride (0.74g) and mix
The mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with water and sulfurized.
It was dried over magnesium chloride and concentrated by evaporation. the resulting mixture
The substance was subjected to silica gel chromatography and chloroform
Elute with a methanol mixture (49:1 v/v) to obtain 4
-[4-(2,4-cyclo-5-sulfamoylben)
zoyl) pipiradin-1-yl]-6-(3,4-dime
Toxyphenyl)-2-methyl-0 rimidine (1,03
g) was obtained. Melting point: 150-160℃ IR (X dis-ru): 1640.1580
cm-1HMR (CDC1a, l;)' 8.0
2 (LH,s), 7.7-7, 4(3H,m>,
6.91 (IH, d, J=8Hz), 6.67
(IH,s). 3.96 (3H,s), 3.92 (3H,s)
, 3.1-4.0 (8H, m) , 2.57 (
3H,s) Example 28 3.4-dihydro-6-(3,4-dimethoxyphenyl
)-3-methyl-4-(2,4,6-drimethylphenylene)
pyrimidine (3.0 g) in IN hydrochloric acid (20 m
1) The middle solution was concentrated by evaporation. Cool the residue on ice and crystallize it.
Ta. The crystals were filtered and dried to give 3,4-dihydro-6-
(3,4-dimethoxyphenyl)-3-methyl-4-(
2,4,6-drimethylphenylimino)pyrimidine salt
The acid salt (2.85 g) was obtained. Melting point: 165-173°C IR (streak seal): 1630.1580
am-1HMR (DMSO-d6.S)' 11.
13 (LHlbr s,), 9-13 (IH, s)
, 7. ．． 58 (LH, d, J=2Hz), 7
．． 42 (IH, dd. J=8Hz, J=41(z), 7.12 (2H
, s), 7.08 (LH, d. J=8Hz), 6.77 (IH, s), 4.
11 (3H,s>, 3.81(68,s),
2.33 (3)1. s>, 2.19 (6)1.
s) Example 29 The following compound was produced in the same manner as in Example 2B. 1) 4,5-dihydro-7-(3,4-dimethoxyf
phenyl)-4-methyl-5-(2,4,6-trimethyl
phenylimino) tetracylo[1,5-a copyrimicin
Hydrochloride melting point: 221°C (decomposition) IR (streak): 1635.1595.2
380 cm'''INMR (DMSO-d6.δ)
: 7.6-6.9 (5)1. m＞. 619 and 580 (each S, total 1), 4.20 and
3.95 (each S. total 38), 3.82 and 376 each
S. Total 6 hours). 232 and 225 (each S, total 3) 1), 2.1
6 and 2.08 (each S, total 6H) East】d''1 and 2.4.6-h N of trimethylphenol (1,03g)
, N-dimethylformamide (20ml) to the middle suspension.
Add sodium hydride (60%, o, 3 og in oil);
Stirred at room temperature for 5 minutes. 4-chloro-6-(3,
4-dimethoxyphenyl)-2-methylpyrimidine (2
,0g) was added and the mixture was stirred at room temperature for 18 hours. melt
The liquid was poured into water (300ml) and extracted with ethyl acetate.
Ta. Wash the organic layer with prine and dry with sodium sulfate.
, evaporated-condensed. Chromatography of the residue on silica gel
Elute with chloroform and extract 6-(3,4-dimethoxychloride).
Cyphenyl)-2-methyl-4-(2,4,6-trimethane)
Thilphenoxy)hyrimidine (1.96 g) was obtained. Melting point: 122-125℃ IR(Xdi'')' 1580 cm-1HM
R(CDCl2.δ): 7.68 (IH, d, J
=2Hz>, 7.50 (18, dd, J=2Hz,
, C3)1z) , 6.93 (2H,s) , 6
．． 90 (IH, d, J=8Hz>, 6.74 (I
H,s), 3.97 (3H,s). 3.93 (3H,s), 2.64 (3H,s)
, 2.33 (3H,s). 2.11 (6H,,) Example 31 The following compound was produced in the same manner as in Example 16 Wl 8.
Built. 6-(3,4-dimethoxyphenyl)-4-(4-ami
Nophenylamino)-2-methylpyrimidine Melting point: 216-217°C IR (striped seal): 1600, 1580
cm'NMR (CDCl2-CD30D, δ): 7
．． 52 (LH, d, J=2Hz>. 7.36 (LH, dd, J=2Hz, 8Hz>,
7.09 (2H, d. J=9Hz), 6.86 (IH, d. J: 8Hz>
, 6.70 (2H, d. J=9Hz), 6.68 (IH, s>, 3.
93 (3H, s), 3.88 (3H, s),
2.57 (3H, s) East mm+3 Also, the following compound was prepared in the same manner as in Example 26 or 27.
Built. 1) 1-acetyl-6-(3,4-dimethoxyphenyl
)-2,3-dimethyl-1,2,3,4-tetrahydro
-4-(2,4,6-trimethylphenylimino)pyri
Midine (0.15 g) was combined with the corresponding 1-unsubstituted compound (
0.41 g) and acetic anhydride (2 ml).
I got more. Melting point: 87-89℃ IR (Stripe 3-L)' 1690.1630
am-''NMR (CDCl2, δ
): 6.80 (4H, br s), 6.
66 (LH, br s), 6.10 (LH, q,
J=6Hz>, 5.41(LH,s), 3.8
4 (38,s), 3.79 (3H,s). 3.09 (38,s), 2.23 (3H,s)
, 2.00 (6H,s). 1.70 (3H,s), 1.39 (3)1. d
, J=6Hz>2) 6-(3,4-dimethoxyphenyl
)-3F0-1-methyl-1-d-ropionyl-1.2,3.4-tetra
Hydro-4-(2,4,6-trimethylphenylimino
) 1.0 rimidine (0.3 g) Corresponding 1-11:
Substituted compound (0.64g) and zolopionyl chloride (0.8g)
m1) was obtained by reacting. Melting point: 178-180℃ IR (sugital) ' 1690.1645.1
630 Cm-'NMR (CDCl2.δ): 7
．． 0-6.6 (5H, m), 5.43 (IH, s
), 5.04 (2H,s), 3.86 (
3H,s), 3.80(3H,s), 3.15
(3H,s) , 2.24 (3H,s) , 2
．． 03 (6H, s), 1.92 (2H, q, J=
7) 1z), 0.94 (3H, t. J=7Hz) Example 33 4-(4-aminophenylamino)-6-(3°4-di
methoxyphenyl)-2-methylpyrimidine (1,0g
) in 1,2-dicooethane (20ml)
methanesulfonyl (0,28ml) and triethyl
Add Ruamine (0,83ml) and leave the mixture for 3 hours.
It refluxed. After cooling, add chloroform (50ml)
Well, I washed it with water. Dry the solution with magnesium sulfate and evaporate
Concentrate and chromatograph on silica gel to remove chloroform.
6-(3,4-dimethoxyphenyl)-
4-(4-mesylaminophenylamino)-2-methyl
Pyrimidine (0.45 g) was obtained. Melting point; 180-185°C IR (sugital am')' 1610.15
9ONMR (CDC13-MeOHd4.δ): 7
．． 7-6.85 (7H, m). 6.83 (IH, s), 3.96 (3H, s)
, 3.93 (3H,s). 2.99 (3H,s), 2.62 (3H,s)
Example 34 The following compound was obtained in the same manner as in Example 33. 1) 3,4-dihydro-6-(3,4-dimethoxyf
phenyl)-2-mesylamino-3-methyl-4-(2,
4,6-Dolimethylphenylimino)pyrimidine Melting point: 260-262°C IR (sudital): 1595.1570
cm-1HMR (DMSO-da, 8)' 9.
35 (IH9br s), 7.60 (IH,br
d, J=2Hz), 7.4-6.9 (4
)1. m). 5.63 <18. s), 3.80 (31(
, s), 3.77 (31, s). 3.30 (3H,s), 3.12 (3
H,s), 2.34 (3H,s). 2.19 (6H,s)] ■1 shadow 1 6-(3,4-dimethoxyphenyl)-3-methyl-1
,2,3,4-tetrahydro-4-(2゜4.6-doli
Methylphenylimino)pyrimidine (1.0g)
Methyl isocyanate (0,
18 ml) was added and the mixture was stirred at room temperature for 3 hours. The mixture was then poured into water (150ml) and the resulting precipitate
Collected. The precipitate was washed with water and dried to obtain 6-(3,4-dimethyl
toxyphenyl)-3=methyl-1-(N-methylcal
Bamoyl 2,3.4-tetrahydro-4-(2,4.6
-Dolimethylphenylimino)pyrimidine (0.99g
) was obtained. Melting point: 184-187℃ IR (sugital): 1675, 1625
, 1600 cm 'NMR (CDCl2, δ)
: 6.9-6.7 (5H, m), 5.43 (I
H,s), 5.03 (2H,s), 4.32
(IH.br,d. J=5Hz), 3.86 (3H.s), 3.
81 (3H.s).

Claims (2)

[Claims] (1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a hydrogen atom, an aryl group optionally substituted with lower alkoxy, lower alkyl, halogen and/or lower alkylthio, Or there are formulas ▲mathematical formulas, chemical formulas, tables, etc.▼(in formulas, ▲mathematical formulas, chemical formulas,
There are tables, etc. ▼ means a N-containing heterocyclic group) R^2 is a group represented by the formula a) = N-R^2_a or b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or -O-R^2_a (in the formula, R^2_a is optionally lower alkyl, lower alkoxy,
Aryl group optionally substituted with amino and/or acylamino, R^2_b is a hydrogen atom or lower alkyl group, formula ▲ has a numerical formula, chemical formula, table, etc. ▼ is optionally acyl and/or ar(lower) alkyl (respectively means an optionally substituted N-containing heterocyclic group)
In the group represented by R^3, R^3 is a hydrogen atom, a lower alkyl group, or when the N atom to which it is bonded is trivalent in the absence of R^3.
^3 is absent, and R^4 is a) an imino group optionally substituted with lower alkyl, aryl or ar(lower) alkyl, or b) a lower alkyl group, hydrogen atom, halogen, lower Alkylthio groups, optionally lower alkyl, aryl, ar(lower)alkyl and/or
or an amino group that may be substituted with acyl, a group represented by the formula ▲ a mathematical formula, a chemical formula, a table, etc. ▼ or a hydrazino group that may optionally be substituted with an acyl ▼ means an N-containing heterocyclic group optionally substituted with acyl and/or a(lower)alkyl), R^5 is a hydrogen atom, a lower alkyl group, optionally a lower alkylamino When the optionally substituted lower alkanoyl group or the N atom to which it is bonded is trivalent without R^5, R^5 does not exist, or R^3 and R^ 4, or R^4 and R^5 may form an N-containing heterocyclic group together with adjacent carbon atoms and nitrogen atoms, and R^6 is a hydrogen atom, a lower alkyl group, a halogen, or optionally Lower alkoxy, lower alkyl, halogen and/or
or an aryl group which may be substituted with lower alkylthio, (2) represents a single bond or a double bond, and (2) in ring A represents 1, 2 or 3 double bonds, respectively. However, R^1 and R^6 are not hydrogen atoms at the same time.] A pyrimidine derivative and a salt thereof. (2) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom, an aryl group optionally substituted with lower alkoxy, lower alkyl, halogen and/or lower alkylthio, or Formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in formulas, ▲ mathematical formulas, chemical formulas,
There are tables, etc. ▼ means a N-containing heterocyclic group) R^2 is a group represented by the formula a) = N-R^2_a or b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or -O-R^2_a (in the formula, R^2_a is optionally lower alkyl, lower alkoxy,
Aryl group optionally substituted with amino and/or acylamino, R^2_b is a hydrogen atom or lower alkyl group, formula ▲ has a numerical formula, chemical formula, table, etc. ▼ is optionally acyl and/or ar(lower) alkyl (respectively means an optionally substituted N-containing heterocyclic group)
In the group represented by R^3, R^3 is a hydrogen atom, a lower alkyl group, or when the N atom to which it is bonded is trivalent in the absence of R^3.
^3 is absent, and R^4 is a) an imino group optionally substituted with lower alkyl, aryl or ar(lower) alkyl, or b) a lower alkyl group, hydrogen atom, halogen, lower Alkylthio groups, optionally lower alkyl, aryl, alk(
Amino groups that may be substituted with (lower) alkyl and/or acyl, formulas▲Mathematical formulas, chemical formulas, tables, etc.▼
A group represented by or a hydrazino group optionally substituted with acyl (Formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼
means an N-containing heterocyclic group optionally substituted with acyl and/or ar(lower)alkyl)
, R^5 is a hydrogen atom, a lower alkyl group, a lower alkanoyl group optionally substituted with lower alkylamino, or when the N atom to which it is bonded is trivalent in the absence of R^5. R^5 is absent, or R^3 and R^4, or R^4 and R^5 together with adjacent carbon atoms and nitrogen atoms form an N-containing heterocyclic group. R^6 may be a hydrogen atom, a lower alkyl group, a halogen, or optionally a lower alkoxy, a lower alkyl, a halogen and/or
or an aryl group which may be substituted with lower alkylthio, (2) represents a single bond or a double bond, and (2) in ring A represents 1, 2 or 3 double bonds, respectively. However, R^1 and R^6 are not hydrogen atoms at the same time.] A pharmaceutical composition for cardiovascular or antiallergic purposes containing a pyrimidine derivative or a salt thereof as an active ingredient.